Reader TTS

ABSTRACT The immediate perioperative period (days before and after surgery) is hypothesized to be crucial in determining long-term cancer outcomes: during this short period, numerous

factors, including excess stress and inflammatory responses, tumour-cell shedding and pro-angiogenic and/or growth factors, might facilitate the progression of pre-existing micrometastases

and the initiation of new metastases, while simultaneously jeopardizing immune control over residual malignant cells. Thus, application of anticancer immunotherapy during this critical time

frame could potentially improve patient outcomes. Nevertheless, this strategy has rarely been implemented to date. In this Perspective, we discuss apparent contraindications for the

perioperative use of cancer immunotherapy, suggest safe immunotherapeutic and other anti-metastatic approaches during this important time frame and specify desired characteristics of such

interventions. These characteristics include a rapid onset of immune activation, avoidance of tumour-promoting effects, no or minimal increase in surgical risk, resilience to stress-related

factors and minimal induction of stress responses. Pharmacological control of excess perioperative stress–inflammatory responses has been shown to be clinically feasible and could

potentially be combined with immune stimulation to overcome the direct pro-metastatic effects of surgery, prevent immune suppression and enhance immunostimulatory responses. Accordingly, we

believe that certain types of immunotherapy, together with interventions to abrogate stress–inflammatory responses, should be evaluated in conjunction with surgery and, for maximal

effectiveness, could be initiated before administration of adjuvant therapies. Such strategies might improve the overall success of cancer treatment. Access through your institution Buy or

subscribe This is a preview of subscription content, access via your institution ACCESS OPTIONS Access through your institution Access Nature and 54 other Nature Portfolio journals Get

Nature+, our best-value online-access subscription $29.99 / 30 days cancel any time Learn more Subscribe to this journal Receive 12 print issues and online access $209.00 per year only

$17.42 per issue Learn more Buy this article * Purchase on SpringerLink * Instant access to full article PDF Buy now Prices may be subject to local taxes which are calculated during checkout

ADDITIONAL ACCESS OPTIONS: * Log in * Learn about institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS THE CANCER-IMMUNE DIALOGUE IN

THE CONTEXT OF STRESS Article 13 October 2023 STRESS AND CANCER: MECHANISMS, SIGNIFICANCE AND FUTURE DIRECTIONS Article 10 September 2021 THERAPY RESISTANCE: OPPORTUNITIES CREATED BY

ADAPTIVE RESPONSES TO TARGETED THERAPIES IN CANCER Article 09 March 2022 REFERENCES * Pudner, R. in _Nursing the Surgical Patient_ 3rd edn 17–34 (Elsevier, 2010). * Horowitz, M., Neeman, E.,

Sharon, E. & Ben-Eliyahu, S. Exploiting the critical perioperative period to improve long-term cancer outcomes. _Nat. Rev. Clin. Oncol._ 12, 213–226 (2015). CAS  PubMed  PubMed Central

  Google Scholar  * Hiller, J. G., Perry, N. J., Poulogiannis, G., Riedel, B. & Sloan, E. K. Perioperative events influence cancer recurrence risk after surgery. _Nat. Rev. Clin. Oncol._

15, 205–218 (2018). PubMed  Google Scholar  * Weitz, J. et al. Dissemination of tumor cells in patients undergoing surgery for colorectal cancer. _Clin. Cancer Res._ 4, 343–348 (1998). CAS

  PubMed  Google Scholar  * Sughrue, M. E., Chang, E. F., Gabriel, R. A., Aghi, M. K. & Blevins, L. S. Excess mortality for patients with residual disease following resection of

pituitary adenomas. _Pituitary_ 14, 276–283 (2011). PubMed  Google Scholar  * Caprotti, R. et al. Free-from-progression period and overall short preoperative immunotherapy with IL-2

increases the survival of pancreatic cancer patients treated with macroscopically radical surgery. _Anticancer Res._ 28, 1951–1954 (2008). CAS  PubMed  Google Scholar  * Badwe, R. et al.

Single-injection depot progesterone before surgery and survival in women with operable breast cancer: a randomized controlled trial. _J. Clin. Oncol._ 29, 2845–2851 (2011). CAS  PubMed 

Google Scholar  * Brivio, F. et al. Pre-operative immunoprophylaxis with interleukin-2 may improve prognosis in radical surgery for colorectal cancer stage B–C. _Anticancer Res._ 26, 599–603

(2006). CAS  PubMed  Google Scholar  * Haldar, R. & Ben-Eliyahu, S. Reducing the risk of post-surgical cancer recurrence: a perioperative anti-inflammatory anti-stress approach. _Future

Oncol._ 14, 1017–1021 (2018). CAS  PubMed  Google Scholar  * Ricon, I., Hanalis-Miller, T., Haldar, R., Jacoby, R. & Ben-Eliyahu, S. Perioperative biobehavioral interventions to prevent

cancer recurrence through combined inhibition of β-adrenergic and cyclooxygenase 2 signaling. _Cancer_ 125, 45–56 (2019). CAS  PubMed  Google Scholar  * Neeman, E., Zmora, O. &

Ben-Eliyahu, S. A new approach to reducing postsurgical cancer recurrence: perioperative targeting of catecholamines and prostaglandins. _Clin. Cancer Res._ 18, 4895–4902 (2012). CAS  PubMed

  PubMed Central  Google Scholar  * Sorski, L. et al. Reducing liver metastases of colon cancer in the context of extensive and minor surgeries through β-adrenoceptors blockade and COX2

inhibition. _Brain Behav. Immun._ 58, 91–98 (2016). CAS  PubMed  Google Scholar  * Seth, R. et al. Surgical stress promotes the development of cancer metastases by a coagulation-dependent

mechanism involving natural killer cells in a murine model. _Ann. Surg._ 258, 158–168 (2013). PubMed  Google Scholar  * Tai, L. H. et al. Preventing postoperative metastatic disease by

inhibiting surgery-induced dysfunction in natural killer cells. _Cancer Res._ 73, 97–107 (2013). CAS  PubMed  Google Scholar  * Hogan, B. V., Peter, M. B., Shenoy, H. G., Horgan, K. &

Hughes, T. A. Surgery induced immunosuppression. _Surgeon_ 9, 38–43 (2011). PubMed  Google Scholar  * Greenfeld, K. et al. Immune suppression while awaiting surgery and following it:

dissociations between plasma cytokine levels, their induced production, and NK cell cytotoxicity. _Brain Behav. Immun._ 21, 503–513 (2007). CAS  PubMed  Google Scholar  * Madden, K. S.,

Sanders, V. M. & Felten, D. L. Catecholamine influences and sympathetic neural modulation of immune responsiveness. _Annu. Rev. Pharmacol. Toxicol._ 35, 417–448 (1995). CAS  PubMed 

Google Scholar  * Padgett, D. A. & Glaser, R. How stress influences the immune response. _Trends Immunol._ 24, 444–448 (2003). CAS  PubMed  Google Scholar  * Forget, P. et al.

Neutrophil:lymphocyte ratio and intraoperative use of ketorolac or diclofenac are prognostic factors in different cohorts of patients undergoing breast, lung, and kidney cancer surgery.

_Ann. Surg. Oncol._ 20, S650–S660 (2013). PubMed  Google Scholar  * Cata, J. P., Guerra, C. E., Chang, G. J., Gottumukkala, V. & Joshi, G. P. Non-steroidal anti-inflammatory drugs in the

oncological surgical population: beneficial or harmful? A systematic review of the literature. _Br. J. Anaesth._ 119, 750–764 (2017). CAS  PubMed  Google Scholar  * Ben-Eliyahu, S.,

Shakhar, G., Rosenne, E., Levinson, Y. & Beilin, B. Hypothermia in barbiturate-anesthetized rats suppresses natural killer cell activity and compromises resistance to tumor metastasis: a

role for adrenergic mechanisms. _Anesthesiology_ 91, 732–740 (1999). CAS  PubMed  Google Scholar  * Beilin, B. et al. Effects of mild perioperative hypothermia on cellular immune responses.

_Anesthesiology_ 89, 1133–1140 (1998). CAS  PubMed  Google Scholar  * Aibiki, M. et al. Effect of moderate hypothermia on systemic and internal jugular plasma IL-6 levels after traumatic

brain injury in humans. _J. Neurotrauma_ 16, 225–232 (1999). CAS  PubMed  Google Scholar  * Nielsen, H. J. Detrimental effects of perioperative blood-transfusion. _Br. J. Surg._ 82, 582–587

(1995). CAS  PubMed  Google Scholar  * Landers, D. F., Hill, G. E., Wong, K. C. & Fox, I. J. Blood transfusion-induced immunomodulation. _Anesth. Analg._ 82, 187–204 (1996). CAS  PubMed

  Google Scholar  * Heaney, A. & Buggy, D. J. Can anaesthetic and analgesic techniques affect cancer recurrence or metastasis? _Br. J. Anaesth._ 109, i17–i28 (2012). PubMed  Google

Scholar  * Filipazzi, P., Huber, V. & Rivoltini, L. Phenotype, function and clinical implications of myeloid-derived suppressor cells in cancer patients. _Cancer Immunol. Immunother._

61, 255–263 (2012). CAS  PubMed  Google Scholar  * Mantovani, A., Marchesi, F., Malesci, A., Laghi, L. & Allavena, P. Tumour-associated macrophages as treatment targets in oncology.

_Nat. Rev. Clin. Oncol._ 14, 399–416 (2017). CAS  PubMed  PubMed Central  Google Scholar  * Lindau, D., Gielen, P., Kroesen, M., Wesseling, P. & Adema, G. J. The immunosuppressive tumour

network: myeloid-derived suppressor cells, regulatory T cells and natural killer T cells. _Immunology_ 138, 105–115 (2013). CAS  PubMed  PubMed Central  Google Scholar  * Lorusso, G. &

Rugg, C. The tumor microenvironment and its contribution to tumor evolution toward metastasis. _Histochem. Cell Biol._ 130, 1091–1103 (2008). CAS  PubMed  Google Scholar  * Lopez-Novoa, J.

M. & Nieto, M. A. Inflammation and EMT: an alliance towards organ fibrosis and cancer progression. _EMBO Mol. Med._ 1, 303–314 (2009). CAS  PubMed  PubMed Central  Google Scholar  * Yu,

H., Pardoll, D. & Jove, R. STATs in cancer inflammation and immunity: a leading role for STAT3. _Nat. Rev. Cancer_ 9, 798–809 (2009). CAS  PubMed  PubMed Central  Google Scholar  *

Mantovani, A., Sozzani, S., Locati, M., Allavena, P. & Sica, A. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. _Trends

Immunol._ 23, 549–555 (2002). CAS  PubMed  Google Scholar  * Cole, S. W., Nagaraja, A. S., Lutgendorf, S. K., Green, P. A. & Sood, A. K. Sympathetic nervous system regulation of the

tumour microenvironment. _Nat. Rev. Cancer_ 15, 563–572 (2015). CAS  PubMed  PubMed Central  Google Scholar  * Shaashua, L. et al. Perioperative COX-2 and β-adrenergic blockade improves

metastatic biomarkers in breast cancer patients in a phase-II randomized trial. _Clin. Cancer Res._ 23, 4651–4661 (2017). CAS  PubMed  PubMed Central  Google Scholar  * Aguirre-Ghiso, J. A.

Models Mechanisms and clinical evidence for cancer dormancy. _Nat. Rev. Cancer_ 7, 834–846 (2007). CAS  PubMed  PubMed Central  Google Scholar  * Jones, P. A. & Baylin, S. B. The

fundamental role of epigenetic events in cancer. _Nat. Rev. Genet._ 3, 415–428 (2002). CAS  PubMed  Google Scholar  * Lambert, A. W., Pattabiraman, D. R. & Weinberg, R. A. Emerging

biological principles of metastasis. _Cell_ 168, 670–691 (2017). CAS  PubMed  PubMed Central  Google Scholar  * Drake, C. G., Jaffee, E. & Pardoll, D. M. Mechanisms of immune evasion by

tumors. _Adv. Immunol._ 90, 51–81 (2006). CAS  PubMed  Google Scholar  * McArdle, C. S., McMillan, D. C. & Hole, D. J. Impact of anastomotic leakage on long-term survival of patients

undergoing curative resection for colorectal cancer. _Br. J. Surg._ 92, 1150–1154 (2005). CAS  PubMed  Google Scholar  * Erinjeri, J. P. et al. Timing of administration of bevacizumab

chemotherapy affects wound healing after chest wall port placement. _Cancer_ 117, 1296–1301 (2011). CAS  PubMed  Google Scholar  * Payne, W. G. et al. Wound healing in patients with cancer.

_Eplasty_ 8, e9 (2008). PubMed  PubMed Central  Google Scholar  * Guan, M., Zhou, Y. P., Sun, J. L. & Chen, S. C. Adverse events of monoclonal antibodies used for cancer therapy. _Biomed

Res. Int._ 2015, 428169 (2015). PubMed  PubMed Central  Google Scholar  * Cohen, S. C., Gabelnick, H. L., Johnson, R. K. & Goldin, A. Effects of cyclophosphamide and adriamycin on the

healing of surgical wounds in mice. _Cancer_ 36, 1277–1281 (1975). CAS  PubMed  Google Scholar  * Engelmann, U., Grimm, K., Gronniger, J., Burger, R. & Jacobi, G. H. Influence of

_cis_-platinum on healing of enterostomies in the rat. _Eur. Urol._ 9, 45–49 (1983). CAS  PubMed  Google Scholar  * Newcombe, J. F. & Chir, M. Effect of intra-arterial nitrogen mustard

infusion on wound healing in rabbits—formation of granulation tissue and wound contraction. _Ann. Surg._ 163, 319–329 (1966). CAS  PubMed  PubMed Central  Google Scholar  * Nissen-Meyer, R.,

Kjellgren, K., Malmio, K., Mansson, B. & Norin, T. Surgical adjuvant chemotherapy: results with one short course with cyclophosphamide after mastectomy for breast cancer. _Cancer_ 41,

2088–2098 (1978). CAS  PubMed  Google Scholar  * Arikan, A. Y., Senel, F. M., Akman, R. Y. & Can, C. Comparison of the effects of various anticancer agents on intestinal anastomosis

after intraperitoneal administration. _Surg. Today_ 29, 741–746 (1999). CAS  PubMed  Google Scholar  * Garfield, J. & Dayan, A. D. Postoperative intracavitary chemotherapy of malignant

gliomas—preliminary study using methotrexate. _J. Neurosurg._ 39, 315–322 (1973). CAS  PubMed  Google Scholar  * Cohn, I., Slack, N. H. & Fisher, B. Complications and toxic

manifestations of surgical adjuvant chemotherapy for breast cancer. _Surg. Gynecol. Obstet._ 127, 1201–1209 (1968). PubMed  Google Scholar  * Rasmussen, L. & Arvin, A.

Chemotherapy-induced immunosuppression. _Environ. Health Perspect._ 43, 21–25 (1982). CAS  PubMed  PubMed Central  Google Scholar  * Harris, J., Sengar, D., Stewart, T. & Hyslop, D. The

effect of immunosuppressive chemotherapy on immune function in patients with malignant disease. _Cancer_ 37, 1058–1069 (1976). CAS  PubMed  Google Scholar  * Galluzzi, L., Buque, A., Kepp,

O., Zitvogel, L. & Kroemer, G. Immunological effects of conventional chemotherapy and targeted anticancer agents. _Cancer Cell_ 28, 690–714 (2015). CAS  PubMed  Google Scholar  *

Zitvogel, L., Apetoh, L., Ghiringhelli, F. & Kroemer, G. Immunological aspects of cancer chemotherapy. _Nat. Rev. Immunol._ 8, 59–73 (2008). CAS  PubMed  Google Scholar  * Ding, Z. C. et

al. Immunosuppressive myeloid cells induced by chemotherapy attenuate antitumor CD4+ T-cell responses through the PD-1–PD-L1 axis. _Cancer Res._ 74, 3441–3453 (2014). CAS  PubMed  PubMed

Central  Google Scholar  * Tsang, Y. W. et al. Chemotherapy-induced immunosuppression is restored by a fermented soybean extract: a proof of concept clinical trial. _Nutr. Res._ 27, 679–684

(2007). CAS  Google Scholar  * Kang, D. H. et al. Significant impairment in immune recovery after cancer treatment. _Nurs. Res._ 58, 105–114 (2009). PubMed  PubMed Central  Google Scholar  *

Verma, R. et al. Lymphocyte depletion and repopulation after chemotherapy for primary breast cancer. _Breast Cancer Res._ 18, 10 (2016). PubMed  PubMed Central  Google Scholar  *

Couzin-Frankel, J. Breakthrough of the year 2013. Cancer immunotherapy. _Science_ 342, 1432–1433 (2013). CAS  PubMed  Google Scholar  * Lee, S. & Margolin, K. Cytokines in cancer

immunotherapy. _Cancers_ 3, 3856–3893 (2011). CAS  PubMed  PubMed Central  Google Scholar  * Kaczanowska, S., Joseph, A. M. & Davila, E. TLR agonists: our best frenemy in cancer

immunotherapy. _J. Leukoc. Biol._ 93, 847–863 (2013). CAS  PubMed  PubMed Central  Google Scholar  * Pardoll, D. M. The blockade of immune checkpoints in cancer immunotherapy. _Nat. Rev.

Cancer_ 12, 252–264 (2012). CAS  PubMed  PubMed Central  Google Scholar  * Mastrangelo, M. J. & Lattime, E. C. Virotherapy clinical trials for regional disease: in situ immune modulation

using recombinant poxvirus vectors. _Cancer Gene Ther._ 9, 1013–1021 (2002). CAS  PubMed  Google Scholar  * Gelderman, K. A., Tomlinson, S., Ross, G. D. & Gorter, A. Complement function

in mAb-mediated cancer immunotherapy. _Trends Immunol._ 25, 158–164 (2004). CAS  PubMed  Google Scholar  * Sippel, T. R. et al. Neutrophil degranulation and immunosuppression in patients

with GBM: restoration of cellular immune function by targeting arginase I. _Clin. Cancer Res._ 17, 6992–7002 (2011). CAS  PubMed  Google Scholar  * Brahmer, J. et al. Nivolumab versus

docetaxel in advanced squamous-cell non-small-cell lung cancer. _N. Engl. J. Med._ 373, 123–135 (2015). CAS  PubMed  PubMed Central  Google Scholar  * Herbst, R. S. et al. Pembrolizumab

versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. _Lancet_ 387, 1540–1550 (2016). CAS  PubMed  Google

Scholar  * Coppin, C. et al. Immunotherapy for advanced renal cell cancer. _Cochrane Database Syst. Rev._ 12, CD001425 (2005). Google Scholar  * Robert, C. et al. Pembrolizumab versus

ipilimumab in advanced melanoma. _N. Engl. J. Med._ 372, 2521–2532 (2015). CAS  PubMed  Google Scholar  * Schmid, P. et al. Atezolizumab and nab-paclitaxel in advanced triple-negative breast

cancer. _N. Engl. J. Med._ 379, 2108–2121 (2018). CAS  PubMed  Google Scholar  * Kojima, T. et al. Pembrolizumab versus chemotherapy as second-line therapy for advanced esophageal cancer:

phase III KEYNOTE-181 study. _J. Clin. Oncol_. 37 (Suppl. 4), 2-2 (2019). Google Scholar  * Borghaei, H. et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer.

_N. Engl. J. Med._ 373, 1627–1639 (2015). CAS  PubMed  PubMed Central  Google Scholar  * Carlino, M. S. & Long, G. V. Is chemotherapy still an option in the treatment of melanoma? _Ann.

Oncol._ 26, 2203–2204 (2015). CAS  PubMed  Google Scholar  * Hamid, O. et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. _N. Engl. J. Med._ 369, 134–144 (2013).

CAS  PubMed  PubMed Central  Google Scholar  * Cohen, J. & Carlet, J. INTERSEPT: an international, multicenter, placebo-controlled trial of monoclonal antibody to human tumor necrosis

factor-α in patients with sepsis. International Sepsis Trial Study Group. _Crit. Care Med._ 24, 1431–1440 (1996). CAS  PubMed  Google Scholar  * Castro, J. E., Sandoval-Sus, J. D., Bole, J.,

Rassenti, L. & Kipps, T. J. Rituximab in combination with high-dose methylprednisolone for the treatment of fludarabine refractory high-risk chronic lymphocytic leukemia. _Leukemia_ 22,

2048–2053 (2008). CAS  PubMed  PubMed Central  Google Scholar  * Wolters, U., Wolf, T., Stützer, H. & Schröder, T. ASA classification and perioperative variables as predictors of

postoperative outcome. _Br. J. Anaesth._ 78, 228–228 (1997). Google Scholar  * National Cancer Institute. Find NCI-supported clinical trials. _NCI_

https://www.cancer.gov/about-cancer/treatment/clinical-trials/search (2020). * US National Library of Medicine._ ClinicalTrials.gov_ https://clinicaltrials.gov/ (2020). * Pollard, J. W.

Tumour-educated macrophages promote tumour progression and metastasis. _Nat. Rev. Cancer_ 4, 71–78 (2004). CAS  PubMed  Google Scholar  * Young, M. R. & Knies, S. Prostaglandin E

production by Lewis lung carcinoma: mechanism for tumor establishment in vivo. _J. Natl Cancer Inst._ 72, 919–922 (1984). CAS  PubMed  Google Scholar  * Beatty, G. L. & Gladney, W. L.

Immune escape mechanisms as a guide for cancer immunotherapy. _Clin. Cancer Res._ 21, 687–692 (2015). CAS  PubMed  Google Scholar  * Dunn, G. P., Bruce, A. T., Ikeda, H., Old, L. J. &

Schreiber, R. D. Cancer immunoediting: from immunosurveillance to tumor escape. _Nat. Immunol._ 3, 991–998 (2002). CAS  PubMed  Google Scholar  * Quail, D. F. & Joyce, J. A.

Microenvironmental regulation of tumor progression and metastasis. _Nat. Med._ 19, 1423–1437 (2013). CAS  PubMed  PubMed Central  Google Scholar  * Steeg, P. S. Tumor metastasis: mechanistic

insights and clinical challenges. _Nat. Med._ 12, 895–904 (2006). CAS  PubMed  Google Scholar  * Rashid, O. M. et al. Resection of the primary tumor improves survival in metastatic breast

cancer by reducing overall tumor burden. _Surgery_ 153, 771–778 (2013). PubMed  Google Scholar  * Hodi, F. S. et al. Improved survival with ipilimumab in patients with metastatic melanoma.

_N. Engl. J. Med._ 363, 711–723 (2010). CAS  PubMed  PubMed Central  Google Scholar  * Lasek, W., Zagozdzon, R. & Jakobisiak, M. Interleukin 12: still a promising candidate for tumor

immunotherapy? _Cancer Immunol. Immunother._ 63, 419–435 (2014). CAS  PubMed  PubMed Central  Google Scholar  * Kanzler, H., Barrat, F. J., Hessel, E. M. & Coffman, R. L. Therapeutic

targeting of innate immunity with Toll-like receptor agonists and antagonists. _Nat. Med._ 13, 552–559 (2007). CAS  PubMed  Google Scholar  * Marano, L. et al. Clinical and immunological

impact of early postoperative enteral immunonutrition after total gastrectomy in gastric cancer patients: a prospective randomized study. _Ann. Surg. Oncol._ 20, 3912–3918 (2013). PubMed 

Google Scholar  * Link, B. K. et al. Oligodeoxynucleotide CpG 7909 delivered as intravenous infusion demonstrates immunologic modulation in patients with previously treated non-Hodgkin

lymphoma. _J. Immunother._ 29, 558–568 (2006). CAS  PubMed  Google Scholar  * Reinartz, S. et al. Evaluation of immunological responses in patients with ovarian cancer treated with the

anti-idiotype vaccine ACA125 by determination of intracellular cytokines—a preliminary report. _Hybridoma_ 18, 41–45 (1999). CAS  PubMed  Google Scholar  * Goldfarb, Y. et al. Improving

postoperative immune status and resistance to cancer metastasis: a combined perioperative approach of immunostimulation and prevention of excessive surgical stress responses. _Ann. Surg._

253, 798–810 (2011). PubMed  Google Scholar  * Glasner, A. et al. Improving survival rates in two models of spontaneous postoperative metastasis in mice by combined administration of a

β-adrenergic antagonist and a cyclooxygenase-2 inhibitor. _J. Immunol._ 184, 2449–2457 (2010). CAS  PubMed  Google Scholar  * Matzner, P. et al. Perioperative treatment with the new

synthetic TLR-4 agonist GLA-SE reduces cancer metastasis without adverse effects. _Int. J. Cancer_ 138, 1754–1764 (2016). CAS  PubMed  Google Scholar  * Park, C. G. et al. Extended release

of perioperative immunotherapy prevents tumor recurrence and eliminates metastases. _Sci. Transl Med._ 10, eaar1916 (2018). PubMed  Google Scholar  * Tai, L. H. et al. Perioperative

influenza vaccination reduces postoperative metastatic disease by reversing surgery-induced dysfunction in natural killer cells. _Clin. Cancer Res._ 19, 5104–5115 (2013). CAS  PubMed  Google

Scholar  * Tai, L. H., Zhang, J. Q. & Auer, R. C. Preventing surgery-induced NK cell dysfunction and cancer metastases with influenza vaccination. _Oncoimmunology_ 2, e26618 (2013).

PubMed  PubMed Central  Google Scholar  * Zou, W. Regulatory T cells, tumour immunity and immunotherapy. _Nat. Rev. Immunol._ 6, 295–307 (2006). CAS  PubMed  Google Scholar  * Basith, S.,

Manavalan, B., Yoo, T. H., Kim, S. G. & Choi, S. Roles of Toll-like receptors in cancer: a double-edged sword for defense and offense. _Arch. Pharm. Res._ 35, 1297–1316 (2012). CAS 

PubMed  Google Scholar  * Hong, I. S. Stimulatory versus suppressive effects of GM-CSF on tumor progression in multiple cancer types. _Exp. Mol. Med._ 48, e242 (2016). CAS  PubMed  PubMed

Central  Google Scholar  * He, W. et al. TLR4 signaling promotes immune escape of human lung cancer cells by inducing immunosuppressive cytokines and apoptosis resistance. _Mol. Immunol._

44, 2850–2859 (2007). CAS  PubMed  Google Scholar  * Kelly, M. G. et al. TLR-4 signaling promotes tumor growth and paclitaxel chemoresistance in ovarian cancer. _Cancer Res._ 66, 3859–3868

(2006). CAS  PubMed  Google Scholar  * Berdel, W. E., Danhauserriedl, S., Steinhauser, G. & Winton, E. F. Various human hematopoietic growth-factors (interleukin-3, GM-CSF, G-CSF)

stimulate clonal growth of nonhematopoietic tumor-cells. _Blood_ 73, 80–83 (1989). CAS  PubMed  Google Scholar  * Dedhar, S., Gaboury, L., Galloway, P. & Eaves, C. Human

granulocyte–macrophage colony-stimulating factor is a growth factor active on a variety of cell types of nonhemopoietic origin. _Proc. Natl Acad. Sci. USA_ 85, 9253–9257 (1988). CAS  PubMed

  PubMed Central  Google Scholar  * Ninck, S. et al. Expression profiles of angiogenic growth factors in squamous cell carcinomas of the head and neck. _Int. J. Cancer_ 106, 34–44 (2003).

CAS  PubMed  Google Scholar  * Levi, B. et al. Stress impairs the efficacy of immune stimulation by CpG-C: potential neuroendocrine mediating mechanisms and significance to tumor metastasis

and the perioperative period. _Brain Behav. Immun._ 56, 209–220 (2016). CAS  PubMed  PubMed Central  Google Scholar  * Nagato, T. & Celis, E. A novel combinatorial cancer immunotherapy

poly-IC and blockade of the PD-1/PD-L1 pathway. _Oncoimmunology_ 3, e28440 (2014). PubMed  PubMed Central  Google Scholar  * Matzner, P. et al. Deleterious synergistic effects of distress

and surgery on cancer metastasis: abolishment through an integrated perioperative immune-stimulating stress-inflammatory-reducing intervention. _Brain Behav. Immun._ 80, 170–178 (2019).

PubMed  Google Scholar  * Zambouri, A. Preoperative evaluation and preparation for anesthesia and surgery. _Hippokratia_ 11, 13–21 (2007). CAS  PubMed  PubMed Central  Google Scholar  *

Fleisher, L. A. et al. 2014 ACC/AHA guideline on perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery: a report of the American College of

Cardiology/American Heart Association Task Force on practice guidelines. _J. Am. Coll. Cardiol._ 64, e77–e137 (2014). PubMed  Google Scholar  * Kwon, S. et al. Importance of perioperative

glycemic control in general surgery: a report from the surgical care and outcomes assessment program. _Ann. Surg._ 257, 8–14 (2013). PubMed  Google Scholar  * Ge, P. L., Du, S. D. & Mao,

Y. L. Advances in preoperative assessment of liver function. _Hepatobiliary Pancreat. Dis. Int._ 13, 361–370 (2014). PubMed  Google Scholar  * King, M. S. Preoperative evaluation. _Am. Fam.

Physician_ 62, 387–396 (2000). CAS  PubMed  Google Scholar  * Tinker, J. H. et al. _Recommendations and Guidelines for Preoperative Evaluation of the Surgical Patient with Emphasis on the

Cardiac Patient for Non-Cardiac Surgery_ (University of Nebraska Medical Center, 2006). * Fry, D. E. Sepsis, systemic inflammatory response, and multiple organ dysfunction: the mystery

continues. _Am. Surg._ 78, 1–8 (2012). PubMed  Google Scholar  * Marik, P. E. & Flemmer, M. The immune response to surgery and trauma: implications for treatment. _J. Trauma Acute Care_

73, 801–808 (2012). CAS  Google Scholar  * Lee, J. et al. Maintenance of colonic homeostasis by distinctive apical TLR9 signalling in intestinal epithelial cells. _Nat. Cell Biol._ 8,

1327–1336 (2006). CAS  PubMed  Google Scholar  * Chen, G. Y. & Nunez, G. Sterile inflammation: sensing and reacting to damage. _Nat. Rev. Immunol._ 10, 826–837 (2010). CAS  PubMed 

PubMed Central  Google Scholar  * Atzpodien, J. et al. IL-2 in combination with IFN-α and 5-FU versus tamoxifen in metastatic renal cell carcinoma: long-term results of a controlled

randomized clinical trial. _Br. J. Cancer_ 85, 1130–1136 (2001). CAS  PubMed  PubMed Central  Google Scholar  * Manegold, C. et al. Randomized phase II trial of a Toll-like receptor 9

agonist oligodeoxynucleotide, PF-3512676, in combination with first-line taxane plus platinum chemotherapy for advanced-stage non-small-cell lung cancer. _J. Clin. Oncol._ 26, 3979–3986

(2008). CAS  PubMed  Google Scholar  * Gridelli, C. et al. Immunotherapy of non-small cell lung cancer: report from an international experts panel meeting of the Italian Association of

Thoracic Oncology. _Expert Opin. Biol. Ther._ 16, 1479–1489 (2016). CAS  PubMed  Google Scholar  * Bertrand, A., Kostine, M., Barnetche, T., Truchetet, M. E. & Schaeverbeke, T. Immune

related adverse events associated with anti-CTLA-4 antibodies: systematic review and meta-analysis. _BMC Med._ 13, 211 (2015). PubMed  PubMed Central  Google Scholar  * Desborough, J. P. The

stress response to trauma and surgery. _Br. J. Anaesth._ 85, 109–117 (2000). CAS  PubMed  Google Scholar  * Goldfarb, Y., Levi, B., Sorski, L., Frenkel, D. & Ben-Eliyahu, S. CpG-C

immunotherapeutic efficacy is jeopardized by ongoing exposure to stress: potential implications for clinical use. _Brain Behav. Immun._ 25, 67–76 (2011). CAS  PubMed  Google Scholar  *

Biesmans, S. et al. Effect of stress and peripheral immune activation on astrocyte activation in transgenic bioluminescent Gfap-luc mice. _Glia_ 63, 1126–1137 (2015). PubMed  Google Scholar

  * Menard, C., Pfau, M. L., Hodes, G. E. & Russo, S. J. Immune and neuroendocrine mechanisms of stress vulnerability and resilience. _Neuropsychopharmacology_ 42, 62–80 (2017). CAS 

PubMed  Google Scholar  * Benbenishty, A. et al. Prophylactic TLR9 stimulation reduces brain metastasis through microglia activation. _PLoS Biol._ 17, e2006859 (2019). CAS  PubMed  PubMed

Central  Google Scholar  * Haldar, R. et al. Perioperative inhibition of β-adrenergic and COX2 signaling in a clinical trial in breast cancer patients improves tumor Ki-67 expression, serum

cytokine levels, and PBMCs transcriptome. _Brain Behav. Immun._ 73, 294–309 (2018). CAS  PubMed  Google Scholar  * Bhatia, S., Tykodi, S. S. & Thompson, J. A. Treatment of metastatic

melanoma: an overview. _Oncology_ 23, 488–496 (2009). PubMed  Google Scholar  * Hayley, S., Merali, Z. & Anisman, H. Stress and cytokine-elicited neuroendocrine and neurotransmitter

sensitization: implications for depressive illness. _Stress_ 6, 19–32 (2003). CAS  PubMed  Google Scholar  * Anisman, H., Poulter, M. O., Gandhi, R., Merali, Z. & Hayley, S. Interferon-α

effects are exaggerated when administered on a psychosocial stressor backdrop: cytokine, corticosterone and brain monoamine variations. _J. Neuroimmunol._ 186, 45–53 (2007). CAS  PubMed 

Google Scholar  * Pollak, Y. & Yirmiya, R. Cytokine-induced changes in mood and behaviour: implications for “depression due to a general medical condition”, immunotherapy and

antidepressive treatment. _Int. J. Neuropsychopharmacol._ 5, 389–399 (2002). CAS  PubMed  Google Scholar  * Lissoni, P. et al. Inhibitory effect of interleukin-3 on interleukin-2-induced

cortisol release in the immunotherapy of cancer. _J. Biol. Regul. Homeost. Agents_ 6, 113–115 (1992). CAS  PubMed  Google Scholar  * Lenczowski, M. J. et al. Central administration of rat

IL-6 induces HPA activation and fever but not sickness behavior in rats. _Am. J. Physiol._ 276, R652–R658 (1999). CAS  PubMed  Google Scholar  * Bernabe, D. G., Tamae, A. C., Biasoli, E. R.

& Oliveira, S. H. Stress hormones increase cell proliferation and regulates interleukin-6 secretion in human oral squamous cell carcinoma cells. _Brain Behav. Immun._ 25, 574–583 (2011).

CAS  PubMed  Google Scholar  * Saphier, D. Neuroendocrine effects of interferon-α in the rat. _Adv. Exp. Med. Biol._ 373, 209–218 (1995). CAS  PubMed  Google Scholar  * Saphier, D., Welch,

J. E. & Chuluyan, H. E. α-Interferon inhibits adrenocortical secretion via Mu 1-opioid receptors in the rat. _Eur. J. Pharmacol._ 236, 183–191 (1993). CAS  PubMed  Google Scholar  *

Goebel, M. U. et al. Acute interferon β1b administration alters hypothalamic–pituitary–adrenal axis activity, plasma cytokines and leukocyte distribution in healthy subjects.

_Psychoneuroendocrinology_ 27, 881–892 (2002). CAS  PubMed  Google Scholar  * Holsboer, F. et al. Acute adrenocortical stimulation by recombinant γ-interferon in human controls. _Life Sci._

42, 1–5 (1988). CAS  PubMed  Google Scholar  * Lepelletier, Y. et al. Toll-like receptor control of glucocorticoid-induced apoptosis in human plasmacytoid predendritic cells (pDCs). _Blood_

116, 3389–3397 (2010). CAS  PubMed  Google Scholar  * Santini-Oliveira, M. et al. Schistosomiasis vaccine candidate Sm14/GLA-SE: phase 1 safety and immunogenicity clinical trial in healthy,

male adults. _Vaccine_ 34, 586–594 (2016). CAS  PubMed  Google Scholar  * Treanor, J. J. et al. Evaluation of safety and immunogenicity of recombinant influenza hemagglutinin

(H5/Indonesia/05/2005) formulated with and without a stable oil-in-water emulsion containing glucopyranosyl-lipid A (SE plus GLA) adjuvant. _Vaccine_ 31, 5760–5765 (2013). CAS  PubMed 

Google Scholar  * Krieg, A. M. CpG still rocks! Update on an accidental drug. _Nucleic Acid. Ther._ 22, 77–89 (2012). CAS  PubMed  Google Scholar  * Zhang, Y., Gu, Y. H., Guo, T. K., Li, Y.

P. & Cai, H. Perioperative immunonutrition for gastrointestinal cancer: a systematic review of randomized controlled trials. _Surg. Oncol._ 21, E87–E95 (2012). PubMed  Google Scholar  *

Calder, P. C. & Kew, S. The immune system: a target for functional foods? _Br. J. Nutr._ 88, S165–S176 (2002). CAS  PubMed  Google Scholar  * Nestlé Health Science. Impact. _Nestlé_

https://www.nestlehealthscience.com/brands/impact/impact (2019). * Caglayan, K. et al. The impact of preoperative immunonutrition and other nutrition models on tumor infiltrative lymphocytes

in colorectal cancer patients. _Am. J. Surg._ 204, 416–421 (2012). PubMed  Google Scholar  * Sorensen, L. D., McCarthy, M., Baumgartner, M. B. & Demars, C. S. Perioperative

immunonutrition in head and neck cancer. _Laryngoscope_ 119, 1358–1364 (2009). CAS  PubMed  Google Scholar  * Turnock, A. et al. Perioperative immunonutrition in well-nourished patients

undergoing surgery for head and neck cancer: evaluation of inflammatory and immunologic outcomes. _Nutrients_ 5, 1186–1199 (2013). CAS  PubMed  PubMed Central  Google Scholar  * Braga, M. et

al. Perioperative immunonutrition in patients undergoing cancer surgery—results of a randomized double-blind phase 3 trial. _Arch. Surg._ 134, 428–433 (1999). CAS  PubMed  Google Scholar  *

Mazzone, P. J. & Arroliga, A. C. Lung cancer: preoperative pulmonary evaluation of the lung resection candidate. _Am. J. Med._ 118, 578–583 (2005). PubMed  Google Scholar  * Epstein, S.

K., Faling, L. J., Daly, B. D. T. & Celli, B. R. Predicting complications after pulmonary resection —preoperative exercise testing vs a multifactorial cardiopulmonary risk index.

_Chest_ 104, 694–700 (1993). CAS  PubMed  Google Scholar  * Smith, T. B., Stonell, C., Purkayastha, S. & Paraskevas, P. Cardiopulmonary exercise testing as a risk assessment method in

non cardio-pulmonary surgery: a systematic review. _Anaesthesia_ 64, 883–893 (2009). CAS  PubMed  Google Scholar  * West, M. A. et al. Cardiopulmonary exercise variables are associated with

postoperative morbidity after major colonic surgery: a prospective blinded observational study. _Br. J. Anaesth._ 112, 665–671 (2014). CAS  PubMed  Google Scholar  * West, M. A. et al.

Validation of preoperative cardiopulmonary exercise testing-derived variables to predict in-hospital morbidity after major colorectal surgery. _Br. J. Surg._ 103, 744–752 (2016). CAS  PubMed

  Google Scholar  * Morikawa, T. et al. Association of CTNNB1 (β-catenin) alterations, body mass index, and physical activity with survival in patients with colorectal cancer. _JAMA_ 305,

1685–1694 (2011). CAS  PubMed  PubMed Central  Google Scholar  * Meyerhardt, J. A. et al. Physical activity and survival after colorectal cancer diagnosis. _J. Clin. Oncol._ 24, 3527–3534

(2006). PubMed  Google Scholar  * Haydon, A. M. M., MacInnis, R. J., English, D. R. & Giles, G. G. Effect of physical activity and body size on survival after diagnosis with colorectal

cancer. _Gut_ 55, 62–67 (2006). CAS  PubMed  PubMed Central  Google Scholar  * Galvao, D. A. & Newton, R. U. Review of exercise intervention studies in cancer patients. _J. Clin. Oncol._

23, 899–909 (2005). PubMed  Google Scholar  * Wang, J. et al. Effect of exercise training intensity on murine T-regulatory cells and vaccination response. _Scand. J. Med. Sci. Sports_ 22,

643–652 (2012). CAS  PubMed  Google Scholar  * Ho, R. T. et al. The effect of t’ai chi exercise on immunity and infections: a systematic review of controlled trials. _J. Altern. Complement.

Med._ 19, 389–396 (2013). PubMed  Google Scholar  * Bote, M. E., Garcia, J. J., Hinchado, M. D. & Ortega, E. Fibromyalgia: anti-inflammatory and stress responses after acute moderate

exercise. _PLoS One_ 8, e74524 (2013). CAS  PubMed  PubMed Central  Google Scholar  * Dranoff, G. Cytokines in cancer pathogenesis and cancer therapy. _Nat. Rev. Cancer_ 4, 11–22 (2004). CAS

  PubMed  Google Scholar  * Lotze, M. T. et al. In vivo administration of purified human interleukin 2. II. Half life, immunologic effects, and expansion of peripheral lymphoid cells in vivo

with recombinant IL 2. _J. Immunol._ 135, 2865–2875 (1985). CAS  PubMed  Google Scholar  * Jiang, T., Zhou, C. & Ren, S. Role of IL-2 in cancer immunotherapy. _Oncoimmunology_ 5,

e1163462 (2016). PubMed  PubMed Central  Google Scholar  * Deehan, D. J., Heys, S. D., Ashby, J. & Eremin, O. Interleukin-2 (IL-2) augments host cellular immune reactivity in the

perioperative period in patients with malignant disease. _Eur. J. Surg. Oncol._ 21, 16–22 (1995). CAS  PubMed  Google Scholar  * Klatte, T. et al. Perioperative immunomodulation with

interleukin-2 in patients with renal cell carcinoma: results of a controlled phase II trial. _Br. J. Cancer_ 95, 1167–1173 (2006). CAS  PubMed  PubMed Central  Google Scholar  * Nichols, P.

H., Ramsden, C. W., Ward, U., Sedman, P. C. & Primrose, J. N. Perioperative immunotherapy with recombinant interleukin-2 in patients undergoing surgery for colorectal-cancer. _Cancer

Res._ 52, 5765–5769 (1992). CAS  PubMed  Google Scholar  * Sedman, P. C., Ramsden, C. W., Brennan, T. G., Giles, G. R. & Guillou, P. J. Effects of low-dose perioperative interferon on

the surgically induced suppression of antitumour immune-responses. _Br. J. Surg._ 75, 976–981 (1988). CAS  PubMed  Google Scholar  * Klatte, T. et al. Pretreatment with interferon-α2a

modulates perioperative immunodysfunction in patients with renal cell carcinoma. _Onkologie_ 31, 28–34 (2008). CAS  PubMed  Google Scholar  * Nagano, H. et al. Hepatic resection followed by

IFN-α and 5-FU for advanced hepatocellular carcinoma with tumor thrombus in the major portal branch. _Hepatogastroenterology_ 54, 172–179 (2007). CAS  PubMed  Google Scholar  * Cascinu, S.

et al. Cytokinetic effects of interferon in colorectal-cancer tumors—implications in the design of the interferon/5-fluorouracil combinations. _Cancer Res._ 53, 5429–5432 (1993). CAS  PubMed

  Google Scholar  * Rajala, P. et al. Perioperative single dose instillation of epirubicin or interferon-α after transurethral resection for the prophylaxis of primary superficial bladder

cancer recurrence: a prospective randomized multicenter study—Finnbladder III long-term results. _J. Urol._ 168, 981–985 (2002). CAS  PubMed  Google Scholar  * Schneider, C. et al.

Perioperative recombinant human granulocyte colony-stimulating factor (Filgrastim) treatment prevents immunoinflammatory dysfunction associated with major surgery. _Ann. Surg._ 239, 75–81

(2004). PubMed  PubMed Central  Google Scholar  * Mels, A. K. et al. Immune-stimulating effects of low-dose perioperative recombinant granulocyte–macrophage colony-stimulating factor in

patients operated on for primary colorectal carcinoma. _Br. J. Surg._ 88, 539–544 (2001). CAS  PubMed  Google Scholar  * Licht, A. K., Schinkel, C., Zedler, S., Schinkel, S. & Faist, E.

Effects of perioperative recombinant human IFN-γ (rHuIFN-γ) application in vivo on T cell response. _J. Interferon Cytokine Res._ 23, 149–154 (2003). CAS  PubMed  Google Scholar  * Badwe, R.

A. et al. Timing of surgery during menstrual cycle and survival of premenopausal women with operable breast cancer. _Lancet_ 337, 1261–1264 (1991). CAS  PubMed  Google Scholar  * Wheeldon,

N. M. et al. Influence of sex-steroid hormones on the regulation of lymphocyte β2-adrenoceptors during the menstrual cycle. _Br. J. Clin. Pharmacol._ 37, 583–588 (1994). CAS  PubMed  PubMed

Central  Google Scholar  * Ben-Eliyahu, S., Page, G. G., Shakhar, G. & Taylor, A. N. Increased susceptibility to metastasis during pro-oestrus/oestrus in rats: possible role of

oestradiol and natural killer cells. _Br. J. Cancer_ 74, 1900–1907 (1996). CAS  PubMed  PubMed Central  Google Scholar  * Shakhar, K., Shakhar, G., Rosenne, E. & Ben-Eliyahu, S. Timing

within the menstrual cycle, sex, and the use of oral contraceptives determine adrenergic suppression of NK cell activity. _Br. J. Cancer_ 83, 1630–1636 (2000). CAS  PubMed  PubMed Central 

Google Scholar  * Ben-Eliyahu, S., Shakhar, G., Shakhar, K. & Melamed, R. Timing within the oestrous cycle modulates adrenergic suppression of NK activity and resistance to metastasis:

possible clinical implications. _Br. J. Cancer_ 83, 1747–1754 (2000). CAS  PubMed  PubMed Central  Google Scholar  * Page, G. G. & Ben-Eliyahu, S. Increased surgery-induced metastasis

and suppressed natural killer cell activity during proestrus/estrus in rats. _Breast Cancer Res. Treat._ 45, 159–167 (1997). CAS  PubMed  Google Scholar  * Neeman, E. & Ben-Eliyahu, S.

Surgery and stress promote cancer metastasis: new outlooks on perioperative mediating mechanisms and immune involvement. _Brain Behav. Immun._ 30, S32–S40 (2013). PubMed  Google Scholar  *

Haldar, R., Ricon, I., Cole, S., Zmora, O. and Ben-Eliyahu, S. Perioperative β-adrenergic blockade and COX2 inhibition in colorectal cancer patients improves pro-metastatic indices in the

excised tumor: EMT, tumor infiltrating lymphocytes (TILs), and gene regulatory pathways. Presented at the PNIRS 24th Annual Scientific Meeting (2017). * Hazut, O. et al. The effect of

β-adrenergic blockade and COX-2 inhibition on healing of colon, muscle, and skin in rats undergoing colonic anastomosis. _Int. J. Clin. Pharmacol. Ther._ 49, 545–554 (2011). CAS  PubMed 

PubMed Central  Google Scholar  * Benjamin, B. et al. Effect of β blocker combined with COX-2 inhibitor on colonic anastomosis in rats. _Int. J. Colorectal Dis._ 25, 1459–1464 (2010). PubMed

  Google Scholar  * Karagiannis, G. S. et al. Neoadjuvant chemotherapy induces breast cancer metastasis through a TMEM-mediated mechanism. _Sci. Transl Med._ 9, eaan0026 (2017). PubMed 

PubMed Central  Google Scholar  * Avraham, R. et al. Synergism between immunostimulation and prevention of surgery-induced immune suppression: an approach to reduce post-operative tumor

progression. _Brain Behav. Immun._ 24, 952–958 (2010). CAS  PubMed  PubMed Central  Google Scholar  * Elenkov, I. J., Papanicolaou, D. A., Wilder, R. L. & Chrousos, G. P. Modulatory

effects of glucocorticoids and catecholamines on human interleukin-12 and interleukin-10 production: clinical implications. _Proc. Assoc. Am. Physicians_ 108, 374–381 (1996). CAS  PubMed 

Google Scholar  * Whalen, M. M. & Bankhurst, A. D. Effects of β-adrenergic receptor activation, cholera toxin and forskolin on human natural killer cell function. _Biochem. J._ 272,

327–331 (1990). CAS  PubMed  PubMed Central  Google Scholar  * Ben-Eliyahu, S., Shakhar, G., Page, G. G., Stefanski, V. & Shakhar, K. Suppression of NK cell activity and of resistance to

metastasis by stress: a role for adrenal catecholamines and β-adrenoceptors. _Neuroimmunomodulation_ 8, 154–164 (2000). CAS  PubMed  Google Scholar  * Diamantstein, T. & Ulmer, A.

Antagonistic action of cyclic-GMP and cyclic-AMP on proliferation of B and T lymphocytes. _Immunology_ 28, 113–119 (1975). CAS  PubMed  PubMed Central  Google Scholar  * Sternberg, E. M.

Neural regulation of innate immunity: a coordinated nonspecific host response to pathogens. _Nat. Rev. Immunol._ 6, 318–328 (2006). CAS  PubMed  PubMed Central  Google Scholar  * Sacedon,

R., Vicente, A., Varas, A., Jimenez, E. & Zapata, A. G. Early differentiation of thymic dendritic cells in the absence of glucocorticoids. _J. Neuroimmunol._ 94, 103–108 (1999). CAS 

PubMed  Google Scholar  * Shaashua, L. et al. Plasma IL-12 levels are suppressed in vivo by stress and surgery through endogenous release of glucocorticoids and prostaglandins but not

catecholamines or opioids. _Psychoneuroendocrinology_ 42, 11–23 (2014). CAS  PubMed  PubMed Central  Google Scholar  * Scheinman, R. I., Cogswell, P. C., Lofquist, A. K. & Baldwin, A. S.

Role of transcriptional activation of IκBαin mediation of immunosuppression by glucocorticoids. _Science_ 270, 283–286 (1995). CAS  PubMed  Google Scholar  * Matyszak, M. K., Citterio, S.,

Rescigno, M. & Ricciardi-Castagnoli, P. Differential effects of corticosteroids during different stages of dendritic cell maturation. _Eur. J. Immunol._ 30, 1233–1242 (2000). CAS  PubMed

  Google Scholar  * Baratelli, F. et al. Prostaglandin E-2 induces FOXP3 gene expression and T regulatory cell function in human CD4+ T cells. _J. Immunol._ 175, 1483–1490 (2005). CAS 

PubMed  Google Scholar  * Sharma, S. et al. Tumor cyclooxygenase-2/prostaglandin E-2-dependent promotion of FOXP3 expression and CD4+CD25+ T regulatory cell activities in lung cancer.

_Cancer Res._ 65, 5211–5220 (2005). CAS  PubMed  Google Scholar  * Stolina, M. et al. Specific inhibition of cyclooxygenase 2 restores antitumor reactivity by altering the balance of IL-10

and IL-12 synthesis. _J. Immunol._ 164, 361–370 (2000). CAS  PubMed  Google Scholar  * Sica, A., Schioppa, T., Mantovani, A. & Allavena, P. Tumour-associated macrophages are a distinct

M2 polarised population promoting tumour progression: potential targets of anti-cancer therapy. _Eur. J. Cancer_ 42, 717–727 (2006). CAS  PubMed  Google Scholar  * Yang, L. et al.

Cancer-associated immunodeficiency and dendritic cell abnormalities mediated by the prostaglandin EP2 receptor. _J. Clin. Invest._ 111, 727–735 (2003). CAS  PubMed  PubMed Central  Google

Scholar  * Melamed, R., Bar-Yosef, S., Shakhar, G., Shakhar, K. & Ben-Eliyahu, S. Suppression of natural killer cell activity and promotion of tumor metastasis by ketamine, thiopental,

and halothane, but not by propofol: mediating mechanisms and prophylactic measures. _Anesth. Analg._ 97, 1331–1339 (2003). CAS  PubMed  Google Scholar  * Markovic, S. N., Knight, P. R. &

Murasko, D. M. Inhibition of interferon stimulation of natural killer cell activity in mice anesthetized with halothane or isoflurane. _Anesthesiology_ 78, 700–706 (1993). CAS  PubMed 

Google Scholar  * Siddiqui, R. A. et al. Anticancer properties of propofol-docosahexaenoate and propofol-eicosapentaenoate on breast cancer cells. _Breast Cancer Res._ 7, R645–R654 (2005).

CAS  PubMed  PubMed Central  Google Scholar  * Sakaguchi, M., Kuroda, Y. & Hirose, M. The antiproliferative effect of lidocaine on human tongue cancer cells with inhibition of the

activity of epidermal growth factor receptor. _Anesth. Analg._ 102, 1103–1107 (2006). CAS  PubMed  Google Scholar  * Mammoto, T. et al. Infiltration anesthetic lidocaine inhibits cancer cell

invasion by modulating ectodomain shedding of heparin-binding epidermal growth factor-like growth factor (HB-EGF). _J. Cell. Physiol._ 192, 351–358 (2002). CAS  PubMed  Google Scholar  *

Martinsson, T. Ropivacaine inhibits serum-induced proliferation of colon adenocarcinoma cells in vitro. _J. Pharmacol. Exp. Ther._ 288, 660–664 (1999). CAS  PubMed  Google Scholar  *

Sessler, D. I., Ben-Eliyahu, S., Mascha, E. J., Parat, M. O. & Buggy, D. J. Can regional analgesia reduce the risk of recurrence after breast cancer? Methodology of a multicenter

randomized trial. _Contemp. Clin. Trials_ 29, 517–526 (2008). PubMed  Google Scholar  * Peterson, P. K. et al. Suppression of human peripheral-blood mononuclear cell-function by methadone

and morphine. _J. Infect. Dis._ 159, 480–487 (1989). CAS  PubMed  Google Scholar  * Chao, C. C., Molitor, T. W., Close, K., Hu, S. X. & Peterson, P. K. Morphine inhibits the release of

tumor-necrosis-factor in human peripheral-blood mononuclear cell-cultures. _Int. J. Immunopharmacol._ 15, 447–453 (1993). CAS  PubMed  Google Scholar  * Afsharimani, B., Cabot, P. &

Parat, M. O. Morphine and tumor growth and metastasis. _Cancer Metastasis Rev._ 30, 225–238 (2011). CAS  PubMed  Google Scholar  * Carr, D. J. J., Gebhardt, B. M. & Paul, D. α-Adrenergic

and Mu-2 opioid receptors are involved in morphine-induced suppression of splenocyte natural-killer activity. _J. Pharmacol. Exp. Ther._ 264, 1179–1186 (1993). CAS  PubMed  Google Scholar 

* Carr, D. J., Mayo, S., Gebhardt, B. M. & Porter, J. Central α-adrenergic involvement in morphine-mediated suppression of splenic natural killer activity. _J. Neuroimmunol._ 53, 53–63

(1994). CAS  PubMed  Google Scholar  * Freier, D. O. & Fuchs, B. A. A mechanism of action for morphine-induced immunosuppression: corticosterone mediates morphine-induced suppression of

natural killer cell activity. _J. Pharmacol. Exp. Ther._ 270, 1127–1133 (1994). CAS  PubMed  Google Scholar  * Sacerdote, P., Manfredi, B., Mantegazza, P. & Panerai, A. E.

Antinociceptive and immunosuppressive effects of opiate drugs: a structure-related activity study. _Br. J. Pharmacol._ 121, 834–840 (1997). CAS  PubMed  PubMed Central  Google Scholar  *

Rojavin, M. et al. Morphine treatment in-vitro or in-vivo decreases phagocytic functions of murine macrophages. _Life Sci._ 53, 997–1006 (1993). CAS  PubMed  Google Scholar  * Khabbazi, S.,

Nassar, Z. D., Goumon, Y. & Parat, M. O. Morphine decreases the pro-angiogenic interaction between breast cancer cells and macrophages in vitro. _Sci. Rep._ 6, 31572 (2016). CAS  PubMed

  PubMed Central  Google Scholar  * Alicea, C., Belkowski, S., Eisenstein, T. K., Adler, M. W. & Rogers, T. J. Inhibition of primary murine macrophage cytokine production in vitro

following treatment with the κ-opioid agonist U50,488H. _J. Neuroimmunol._ 64, 83–90 (1996). CAS  PubMed  Google Scholar  * Wheatley, D. N. Controlling cancer by restricting arginine

availability—arginine-catabolizing enzymes as anticancer. _Anticancer Drugs_ 15, 825–833 (2004). CAS  PubMed  Google Scholar  * Feun, L. & Savaraj, N. Pegylated arginine deiminase: a

novel anticancer enzyme agent. _Expert Opin. Investig. Drugs_ 15, 815–822 (2006). CAS  PubMed  PubMed Central  Google Scholar  * Izzo, F. et al. Pegylated arginine deiminase treatment of

patients with unresectable hepatocellular carcinoma: results from phase I/II studies. _J. Clin. Oncol._ 22, 1815–1822 (2004). CAS  PubMed  Google Scholar  * Nanthakumaran, S., Brown, I.,

Heys, S. D. & Schofield, A. C. Inhibition of gastric cancer cell growth by arginine: molecular mechanisms of action. _Clin. Nutr._ 28, 65–70 (2009). CAS  PubMed  Google Scholar  *

Albina, J. E., Caldwell, M. D., Henry, W. L. Jr. & Mills, C. D. Regulation of macrophage functions by L-arginine. _J. Exp. Med._ 169, 1021–1029 (1989). CAS  PubMed  Google Scholar  *

Park, K. G., Hayes, P. D., Garlick, P. J., Sewell, H. & Eremin, O. Stimulation of lymphocyte natural cytotoxicity by L-arginine. _Lancet_ 337, 645–646 (1991). CAS  PubMed  Google Scholar

  * Cho-Chung, Y. S., Clair, T., Bodwin, J. S. & Berghoffer, B. Growth arrest and morphological change of human breast cancer cells by dibutyryl cyclic AMP and L-arginine. _Science_ 214,

77–79 (1981). CAS  PubMed  Google Scholar  * Synakiewicz, A., Stachowicz-Stencel, T. & Adamkiewicz-Drozynska, E. The role of arginine and the modified arginine deiminase enzyme ADI-PEG

20 in cancer therapy with special emphasis on phase I/II clinical trials. _Expert Opin. Investig. Drugs_ 23, 1517–1529 (2014). CAS  PubMed  Google Scholar  * Samid, D., Yeh, A. &

Prasanna, P. Induction of erythroid differentiation and fetal hemoglobin production in human leukemic cells treated with phenylacetate. _Blood_ 80, 1576–1581 (1992). CAS  PubMed  Google

Scholar  * Samid, D. et al. Selective activity of phenylacetate against malignant gliomas: resemblance to fetal brain damage in phenylketonuria. _Cancer Res._ 54, 891–895 (1994). CAS  PubMed

  Google Scholar  * Samid, D., Shack, S. & Myers, C. E. Selective growth arrest and phenotypic reversion of prostate cancer cells in vitro by nontoxic pharmacological concentrations of

phenylacetate. _J. Clin. Invest._ 91, 2288–2295 (1993). CAS  PubMed  PubMed Central  Google Scholar  * DeBerardinis, R. J. & Cheng, T. Q’s next: the diverse functions of glutamine in

metabolism, cell biology and cancer. _Oncogene_ 29, 313–324 (2010). CAS  PubMed  Google Scholar  * Salaun, B., Coste, I., Rissoan, M. C., Lebecque, S. J. & Renno, T. TLR3 can directly

trigger apoptosis in human cancer cells. _J. Immunol._ 176, 4894–4901 (2006). CAS  PubMed  Google Scholar  * Adams, S. Toll-like receptor agonists in cancer therapy. _Immunotherapy_ 1,

949–964 (2009). CAS  PubMed  Google Scholar  * Ho, V. et al. TLR3 agonist and sorafenib combinatorial therapy promotes immune activation and controls hepatocellular carcinoma progression.

_Oncotarget_ 6, 27252–27266 (2015). PubMed  PubMed Central  Google Scholar  * Robinson, R. A. et al. Phase 1–2 trial of multiple-dose polyriboinosinic-polyribocytidylic acid in patients with

leukemia or solid tumors. _J. Natl Cancer Inst._ 57, 599–602 (1976). CAS  PubMed  Google Scholar  * Alderson, M. R., McGowan, P., Baldridge, J. R. & Probst, P. TLR4 agonists as

immunomodulatory agents. _J. Endotoxin Res._ 12, 313–319 (2006). CAS  PubMed  Google Scholar  * Coler, R. N. et al. Development and characterization of synthetic glucopyranosyl lipid

adjuvant system as a vaccine adjuvant. _PLoS One_ 6, e16333 (2011). CAS  PubMed  PubMed Central  Google Scholar  * Yusuf, N. et al. Protective role of toll-like receptor 4 during the

initiation stage of cutaneous chemical carcinogenesis. _Cancer Res._ 68, 615–622 (2008). CAS  PubMed  PubMed Central  Google Scholar  * Spaner, D. E. et al. Immunomodulatory effects of

toll-like receptor-7 activation on chronic lymphocytic leukemia cells. _Leukemia_ 20, 286–295 (2006). CAS  PubMed  Google Scholar  * Dummer, R. et al. An exploratory study of systemic

administration of the Toll-like receptor-7 agonist 852A in patients with refractory metastatic melanoma. _Clin. Cancer Res._ 14, 856–864 (2008). CAS  PubMed  Google Scholar  * Krieg, A. M.

CpG motifs in bacterial DNA and their immune effects. _Annu. Rev. Immunol._ 20, 709–760 (2002). CAS  PubMed  Google Scholar  * Krieg, A. M. Therapeutic potential of Toll-like receptor 9

activation. _Nat. Rev. Drug Discov._ 5, 471–484 (2006). CAS  PubMed  Google Scholar  * Gruenbacher, G. et al. IL-2 costimulation enables statin-mediated activation of human NK cells,

preferentially through a mechanism involving CD56+ dendritic cells. _Cancer Res._ 70, 9611–9620 (2010). CAS  PubMed  Google Scholar  * Van Gool, F. et al. Interleukin-5-producing group 2

innate lymphoid cells control eosinophilia induced by interleukin-2 therapy. _Blood_ 124, 3572–3576 (2014). PubMed  PubMed Central  Google Scholar  * Williams, M. A., Tyznik, A. J. &

Bevan, M. J. Interleukin-2 signals during priming are required for secondary expansion of CD8+ memory T cells. _Nature_ 441, 890–893 (2006). CAS  PubMed  PubMed Central  Google Scholar  * Le

Bon, A. et al. Cross-priming of CD8+ T cells stimulated by virus-induced type I interferon. _Nat. Immunol._ 4, 1009–1015 (2003). PubMed  Google Scholar  * Trinchieri, G. & Santoli, D.

Anti-viral activity induced by culturing lymphocytes with tumor-derived or virus-transformed cells—enhancement of human natural killer cell activity by interferon and antagonistic inhibition

of susceptibility of target-cells to lysis. _J. Exp. Med._ 147, 1314–1333 (1978). CAS  PubMed  Google Scholar  * Bogdan, C., Mattner, J. & Schleicher, U. The role of type I interferons

in non-viral infections. _Immunol. Rev._ 202, 33–48 (2004). CAS  PubMed  Google Scholar  * Okanoue, T. et al. Side effects of high-dose interferon therapy for chronic hepatitis C. _J.

Hepatol._ 25, 283–291 (1996). CAS  PubMed  Google Scholar  * Naik, S. et al. Curative one-shot systemic virotherapy in murine myeloma. _Leukemia_ 26, 1870–1878 (2012). CAS  PubMed  PubMed

Central  Google Scholar  * Kottke, T. et al. Broad antigenic coverage induced by vaccination with virus-based cDNA libraries cures established tumors. _Nat. Med._ 17, 854–859 (2011). CAS 

PubMed  PubMed Central  Google Scholar  * Russell, S. J., Peng, K. W. & Bell, J. C. Oncolytic virotherapy. _Nat. Biotechnol._ 30, 658–670 (2012). CAS  PubMed  PubMed Central  Google

Scholar  * Andtbacka, R. H. I. et al. Final analyses of OPTiM: a randomized phase III trial of talimogene laherparepvec versus granulocyte–macrophage colony-stimulating factor in

unresectable stage III–IV melanoma. _J. Immunother. Cancer_ 7, 145 (2019). PubMed  PubMed Central  Google Scholar  * Carthon, B. C. et al. Preoperative CTLA-4 blockade: tolerability and

immune monitoring in the setting of a presurgical clinical trial. _Clin. Cancer Res._ 16, 2861–2871 (2010). CAS  PubMed  PubMed Central  Google Scholar  * Shrikant, P., Khoruts, A. &

Mescher, M. F. CTLA-4 blockade reverses CD8+ T cell tolerance to tumor by a CD4+ T cell-and IL-2-dependent mechanism. _Immunity_ 11, 483–493 (1999). CAS  PubMed  Google Scholar  * Phan, G.

Q. et al. Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. _Proc. Natl Acad. Sci. USA_ 100, 8372–8377

(2003). CAS  PubMed  PubMed Central  Google Scholar  * Lee, C. K. et al. Checkpoint inhibitors in metastatic EGFR-mutated non-small cell lung cancer—a meta-analysis. _J. Thorac. Oncol._ 12,

403–407 (2017). PubMed  Google Scholar  * Dong, H. et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. _Nat. Med._ 8, 793–800 (2002). CAS 

PubMed  Google Scholar  * Moslehi, J. J., Salem, J. E., Sosman, J. A., Lebrun-Vignes, B. & Johnson, D. B. Increased reporting of fatal immune checkpoint inhibitor-associated myocarditis.

_Lancet_ 391, 933 (2018). PubMed  PubMed Central  Google Scholar  * Ramalingam, S. et al. Long-term OS for patients with advanced NSCLC enrolled in the KEYNOTE-001 study of pembrolizumab.

_J. Thorac. Oncol._ 11, S241–S242 (2016). Google Scholar  * Valzasina, B. et al. Triggering of OX40 (CD134) on CD4+CD25+ T cells blocks their inhibitory activity: a novel regulatory role for

OX40 and its comparison with GITR. _Blood_ 105, 2845–2851 (2005). CAS  PubMed  Google Scholar  * Vu, M. D. et al. OX40 costimulation turns off Foxp3+ tregs. _Blood_ 110, 2501–2510 (2007).

CAS  PubMed  PubMed Central  Google Scholar  * Lei, F. Y. et al. Regulation of A1 by OX40 contributes to CD8+ T cell survival and anti-tumor activity. _PLoS One_ 8, e70635 (2013). CAS 

PubMed  PubMed Central  Google Scholar  * Song, J. X., So, T. & Croft, M. Activation of NF-κB1 by OX40 contributes to antigen-driven T cell expansion and survival. _J. Immunol._ 180,

7240–7248 (2008). CAS  PubMed  Google Scholar  * Curti, B. D. et al. OX40 is a potent immune-stimulating target in late-stage cancer patients. _Cancer Res._ 73, 7189–7198 (2013). CAS  PubMed

  PubMed Central  Google Scholar  * Weinberg, A. D. et al. Anti-OX40 (CD134) administration to nonhuman primates: immunostimulatory effects and toxicokinetic study. _J. Immunother._ 29,

575–585 (2006). CAS  PubMed  Google Scholar  * Montler, R. et al. OX40, PD-1 and CTLA-4 are selectively expressed on tumor-infiltrating T cells in head and neck cancer. _Clin. Transl

Immunol._ 5, e70 (2016). Google Scholar  Download references ACKNOWLEDGEMENTS The authors thank the US National Cancer Institute (NCI), the Israel Ministry of Science and the Israeli Science

Foundation for research funding. REVIEWER INFORMATION _Nature Reviews Clinical Oncology_ thanks Bernhard Riedel, Daniel Sessler, Marie-Odile Parat and Rebecca Auer for their contribution to

the peer review of this work. AUTHOR INFORMATION Author notes * These authors contributed equally: Pini Matzner, Elad Sandbank. AUTHORS AND AFFILIATIONS * Neuro-Immunology Research Unit,

School of Psychological Sciences, Tel-Aviv University, Tel Aviv-Yafo, Israel Pini Matzner, Elad Sandbank & Shamgar Ben-Eliyahu * Department of Hematology and Oncology, Kaiser Permanente

Northern California, San Francisco, CA, USA Elad Neeman * Surgical Department, Yitzhak Shamir Medical Center, Be’er Ya’akov, Israel Oded Zmora * Department of Anesthesiology and

Perioperative Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Vijaya Gottumukkala * Sagol School of Neuroscience, Tel Aviv University, Tel Aviv-Yafo, Israel

Shamgar Ben-Eliyahu Authors * Pini Matzner View author publications You can also search for this author inPubMed Google Scholar * Elad Sandbank View author publications You can also search

for this author inPubMed Google Scholar * Elad Neeman View author publications You can also search for this author inPubMed Google Scholar * Oded Zmora View author publications You can also

search for this author inPubMed Google Scholar * Vijaya Gottumukkala View author publications You can also search for this author inPubMed Google Scholar * Shamgar Ben-Eliyahu View author

publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS All authors contributed equally to all aspects of the article. CORRESPONDING AUTHOR Correspondence to

Shamgar Ben-Eliyahu. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing interests. ADDITIONAL INFORMATION PUBLISHER’S NOTE Springer Nature remains neutral with regard

to jurisdictional claims in published maps and institutional affiliations. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Matzner, P., Sandbank, E.,

Neeman, E. _et al._ Harnessing cancer immunotherapy during the unexploited immediate perioperative period. _Nat Rev Clin Oncol_ 17, 313–326 (2020). https://doi.org/10.1038/s41571-019-0319-9

Download citation * Accepted: 05 December 2019 * Published: 17 February 2020 * Issue Date: May 2020 * DOI: https://doi.org/10.1038/s41571-019-0319-9 SHARE THIS ARTICLE Anyone you share the

following link with will be able to read this content: Get shareable link Sorry, a shareable link is not currently available for this article. Copy to clipboard Provided by the Springer

Nature SharedIt content-sharing initiative