Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Perspective
  • Published:

Harnessing cancer immunotherapy during the unexploited immediate perioperative period

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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Interactions between perioperative physiological responses to surgery, the immune system and immunotherapy, and the associated effects on cancer growth.

Similar content being viewed by others

References

  1. Pudner, R. in Nursing the Surgical Patient 3rd edn 17–34 (Elsevier, 2010).

  2. 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 

  3. 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 

  4. 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 

  5. 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 

  6. 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 

  7. 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 

  8. 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 

  9. 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 

  10. 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 

  11. 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 

  12. 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 

  13. 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 

  14. 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 

  15. 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 

  16. 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 

  17. 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 

  18. Padgett, D. A. & Glaser, R. How stress influences the immune response. Trends Immunol. 24, 444–448 (2003).

    CAS  PubMed  Google Scholar 

  19. 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 

  20. 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 

  21. 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 

  22. Beilin, B. et al. Effects of mild perioperative hypothermia on cellular immune responses. Anesthesiology 89, 1133–1140 (1998).

    CAS  PubMed  Google Scholar 

  23. 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 

  24. Nielsen, H. J. Detrimental effects of perioperative blood-transfusion. Br. J. Surg. 82, 582–587 (1995).

    CAS  PubMed  Google Scholar 

  25. 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 

  26. 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 

  27. 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 

  28. 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 

  29. 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 

  30. 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 

  31. 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 

  32. 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 

  33. 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 

  34. 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 

  35. 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 

  36. 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 

  37. 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 

  38. 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 

  39. Drake, C. G., Jaffee, E. & Pardoll, D. M. Mechanisms of immune evasion by tumors. Adv. Immunol. 90, 51–81 (2006).

    CAS  PubMed  Google Scholar 

  40. 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 

  41. 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 

  42. Payne, W. G. et al. Wound healing in patients with cancer. Eplasty 8, e9 (2008).

    PubMed  PubMed Central  Google Scholar 

  43. 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 

  44. 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 

  45. 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 

  46. 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 

  47. 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 

  48. 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 

  49. 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 

  50. 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 

  51. Rasmussen, L. & Arvin, A. Chemotherapy-induced immunosuppression. Environ. Health Perspect. 43, 21–25 (1982).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 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 

  53. 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 

  54. Zitvogel, L., Apetoh, L., Ghiringhelli, F. & Kroemer, G. Immunological aspects of cancer chemotherapy. Nat. Rev. Immunol. 8, 59–73 (2008).

    CAS  PubMed  Google Scholar 

  55. 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 

  56. 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 

  57. Kang, D. H. et al. Significant impairment in immune recovery after cancer treatment. Nurs. Res. 58, 105–114 (2009).

    PubMed  PubMed Central  Google Scholar 

  58. 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 

  59. Couzin-Frankel, J. Breakthrough of the year 2013. Cancer immunotherapy. Science 342, 1432–1433 (2013).

    CAS  PubMed  Google Scholar 

  60. Lee, S. & Margolin, K. Cytokines in cancer immunotherapy. Cancers 3, 3856–3893 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 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 

  62. Pardoll, D. M. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 12, 252–264 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 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 

  64. 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 

  65. 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 

  66. 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 

  67. 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 

  68. Coppin, C. et al. Immunotherapy for advanced renal cell cancer. Cochrane Database Syst. Rev. 12, CD001425 (2005).

    Google Scholar 

  69. Robert, C. et al. Pembrolizumab versus ipilimumab in advanced melanoma. N. Engl. J. Med. 372, 2521–2532 (2015).

    CAS  PubMed  Google Scholar 

  70. 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 

  71. 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 

  72. 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 

  73. 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 

  74. 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 

  75. 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 

  76. 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 

  77. 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 

  78. National Cancer Institute. Find NCI-supported clinical trials. NCI https://www.cancer.gov/about-cancer/treatment/clinical-trials/search (2020).

  79. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ (2020).

  80. Pollard, J. W. Tumour-educated macrophages promote tumour progression and metastasis. Nat. Rev. Cancer 4, 71–78 (2004).

    CAS  PubMed  Google Scholar 

  81. 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 

  82. 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 

  83. 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 

  84. 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 

  85. Steeg, P. S. Tumor metastasis: mechanistic insights and clinical challenges. Nat. Med. 12, 895–904 (2006).

    CAS  PubMed  Google Scholar 

  86. 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 

  87. 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 

  88. 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 

  89. 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 

  90. 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 

  91. 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 

  92. 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 

  93. 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 

  94. 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 

  95. 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 

  96. 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 

  97. 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 

  98. 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 

  99. Zou, W. Regulatory T cells, tumour immunity and immunotherapy. Nat. Rev. Immunol. 6, 295–307 (2006).

    CAS  PubMed  Google Scholar 

  100. 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 

  101. 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 

  102. 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 

  103. 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 

  104. 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 

  105. 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 

  106. 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 

  107. 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 

  108. 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 

  109. 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 

  110. Zambouri, A. Preoperative evaluation and preparation for anesthesia and surgery. Hippokratia 11, 13–21 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. 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 

  112. 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 

  113. 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 

  114. King, M. S. Preoperative evaluation. Am. Fam. Physician 62, 387–396 (2000).

    CAS  PubMed  Google Scholar 

  115. 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).

  116. Fry, D. E. Sepsis, systemic inflammatory response, and multiple organ dysfunction: the mystery continues. Am. Surg. 78, 1–8 (2012).

    PubMed  Google Scholar 

  117. 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 

  118. 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 

  119. 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 

  120. 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 

  121. 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 

  122. 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 

  123. 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 

  124. Desborough, J. P. The stress response to trauma and surgery. Br. J. Anaesth. 85, 109–117 (2000).

    CAS  PubMed  Google Scholar 

  125. 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 

  126. 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 

  127. 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 

  128. Benbenishty, A. et al. Prophylactic TLR9 stimulation reduces brain metastasis through microglia activation. PLoS Biol. 17, e2006859 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. 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 

  130. Bhatia, S., Tykodi, S. S. & Thompson, J. A. Treatment of metastatic melanoma: an overview. Oncology 23, 488–496 (2009).

    PubMed  Google Scholar 

  131. 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 

  132. 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 

  133. 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 

  134. 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 

  135. 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 

  136. 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 

  137. Saphier, D. Neuroendocrine effects of interferon-α in the rat. Adv. Exp. Med. Biol. 373, 209–218 (1995).

    CAS  PubMed  Google Scholar 

  138. 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 

  139. 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 

  140. Holsboer, F. et al. Acute adrenocortical stimulation by recombinant γ-interferon in human controls. Life Sci. 42, 1–5 (1988).

    CAS  PubMed  Google Scholar 

  141. 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 

  142. 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 

  143. 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 

  144. Krieg, A. M. CpG still rocks! Update on an accidental drug. Nucleic Acid. Ther. 22, 77–89 (2012).

    CAS  PubMed  Google Scholar 

  145. 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 

  146. Calder, P. C. & Kew, S. The immune system: a target for functional foods? Br. J. Nutr. 88, S165–S176 (2002).

    CAS  PubMed  Google Scholar 

  147. Nestlé Health Science. Impact. Nestlé https://www.nestlehealthscience.com/brands/impact/impact (2019).

  148. 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 

  149. 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 

  150. 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 

  151. 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 

  152. 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 

  153. 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 

  154. 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 

  155. 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 

  156. 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 

  157. 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 

  158. Meyerhardt, J. A. et al. Physical activity and survival after colorectal cancer diagnosis. J. Clin. Oncol. 24, 3527–3534 (2006).

    PubMed  Google Scholar 

  159. 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 

  160. Galvao, D. A. & Newton, R. U. Review of exercise intervention studies in cancer patients. J. Clin. Oncol. 23, 899–909 (2005).

    PubMed  Google Scholar 

  161. 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 

  162. 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 

  163. 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 

  164. Dranoff, G. Cytokines in cancer pathogenesis and cancer therapy. Nat. Rev. Cancer 4, 11–22 (2004).

    CAS  PubMed  Google Scholar 

  165. 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 

  166. Jiang, T., Zhou, C. & Ren, S. Role of IL-2 in cancer immunotherapy. Oncoimmunology 5, e1163462 (2016).

    PubMed  PubMed Central  Google Scholar 

  167. 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 

  168. 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 

  169. 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 

  170. 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 

  171. 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 

  172. 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 

  173. 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 

  174. 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 

  175. 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 

  176. 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 

  177. 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 

  178. 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 

  179. 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 

  180. 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 

  181. 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 

  182. 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 

  183. 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 

  184. 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 

  185. 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).

  186. 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 

  187. 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 

  188. 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 

  189. 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 

  190. 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 

  191. 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 

  192. 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 

  193. 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 

  194. 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 

  195. 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 

  196. 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 

  197. 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 

  198. 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 

  199. 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 

  200. 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 

  201. 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 

  202. 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 

  203. 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 

  204. 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 

  205. 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 

  206. 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 

  207. 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 

  208. 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 

  209. 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 

  210. 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 

  211. 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 

  212. 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 

  213. Afsharimani, B., Cabot, P. & Parat, M. O. Morphine and tumor growth and metastasis. Cancer Metastasis Rev. 30, 225–238 (2011).

    CAS  PubMed  Google Scholar 

  214. 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 

  215. 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 

  216. 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 

  217. 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 

  218. 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 

  219. 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 

  220. 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 

  221. Wheatley, D. N. Controlling cancer by restricting arginine availability—arginine-catabolizing enzymes as anticancer. Anticancer Drugs 15, 825–833 (2004).

    CAS  PubMed  Google Scholar 

  222. 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 

  223. 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 

  224. 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 

  225. 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 

  226. 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 

  227. 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 

  228. 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 

  229. 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 

  230. 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 

  231. 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 

  232. 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 

  233. 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 

  234. Adams, S. Toll-like receptor agonists in cancer therapy. Immunotherapy 1, 949–964 (2009).

    CAS  PubMed  Google Scholar 

  235. 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 

  236. 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 

  237. 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 

  238. 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 

  239. 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 

  240. 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 

  241. 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 

  242. Krieg, A. M. CpG motifs in bacterial DNA and their immune effects. Annu. Rev. Immunol. 20, 709–760 (2002).

    CAS  PubMed  Google Scholar 

  243. Krieg, A. M. Therapeutic potential of Toll-like receptor 9 activation. Nat. Rev. Drug Discov. 5, 471–484 (2006).

    CAS  PubMed  Google Scholar 

  244. 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 

  245. 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 

  246. 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 

  247. 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 

  248. 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 

  249. 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 

  250. 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 

  251. Naik, S. et al. Curative one-shot systemic virotherapy in murine myeloma. Leukemia 26, 1870–1878 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  252. 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 

  253. Russell, S. J., Peng, K. W. & Bell, J. C. Oncolytic virotherapy. Nat. Biotechnol. 30, 658–670 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  254. 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 

  255. 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 

  256. 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 

  257. 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 

  258. 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 

  259. 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 

  260. 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 

  261. 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 

  262. 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 

  263. Vu, M. D. et al. OX40 costimulation turns off Foxp3+ tregs. Blood 110, 2501–2510 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  264. 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 

  265. 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 

  266. 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 

  267. 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 

  268. 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

Authors and Affiliations

Authors

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

Check for updates. Verify currency and authenticity via CrossMark

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:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41571-019-0319-9

This article is cited by

Search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer