Top

Published in:

Open Access 01-11-2018 | Translational Research and Biomarkers

Natural Killer Cell IFNγ Secretion is Profoundly Suppressed Following Colorectal Cancer Surgery

Authors: Leonard Angka, MSc, Andre B. Martel, MD, Marisa Kilgour, BSc, Ahwon Jeong, BSc, Manahil Sadiq, BSc, Christiano Tanese de Souza, DVet, Laura Baker, MD, Michael A. Kennedy, PhD, Natasha Kekre, MD, MPH, Rebecca C. Auer, MD, MSc

Published in: Annals of Surgical Oncology | Issue 12/2018

Abstract

Background

Surgical stress results in a significant reduction in natural killer (NK) cell cytotoxicity (NKC), which has been linked to postoperative cancer metastases. However, few studies have measured the impact of surgical stress upon NK cell IFNγ secretion (NKA), a cytokine with essential roles in controlling infection and metastases. The objective of this study was to investigate the impact of surgical stress on NKA in colorectal cancer (CRC) surgery patients.

Methods

Peripheral blood was collected from CRC surgery patients (n = 42) preoperatively and on postoperative day (POD) 1, 3, 5, 28, and 56. Healthy donor blood (n = 27) was collected for controls. We assessed NKA by production of IFNγ following whole blood cytokine stimulation, NKC by ⁵¹Cr-release assay, and immune cell profiling by flow cytometry.

Results

The mean reduction in NKA on POD1 compared with baseline was 83.1% (standard deviation 25.2%; confidence interval 75–91), and therefore the study met the primary endpoint of demonstrating a > 75% decrease in a cohort of CRC surgery patients (p < 0.0001). The profound and universal suppression of NKA persisted with 65.5% (19/29) and 33.3% (4/12) of patients with levels measuring < 75% of baseline on POD28 and POD56 respectively. The NKC was significantly reduced on POD1, but the degree was less pronounced (24.6%, p = 0.0024). Immune cell profiling did not reveal differences in the absolute number of NK cells (CD3⁻CD56⁺) or the ratio of CD56^dim-to-CD56^bright subsets.

Conclusions

NKA is significantly suppressed for up to two months following surgery in CRC patients, a degree of surgery-induced immunosuppression far worse than previously reported.

Available only for authorised users

Lanier LL. NK cell recognition. Annu Rev Immunol. 2005;23(1):225–74. https://doi.org/10.1146/annurev.immunol.23.021704.115526.CrossRefPubMed

Ishigami S, Natsugoe S, Tokuda K, et al. Prognostic value of intratumoral natural killer cells in gastric carcinoma. Cancer. 2000;88(3):577–83. https://doi.org/10.1002/(sici)1097-0142(20000201)88:3%3c577::aid-cncr13%3e3.0.co;2-v.CrossRefPubMed

Coca S, Perez-Piqueras J, Martinez D, et al. The prognostic significance of intratumoral natural killer cells in patients with colorectal carcinoma. Cancer. 1997;79(12):2320–8. https://doi.org/10.1002/(sici)1097-0142(19970615)79:12%3c2320::aid-cncr5%3e3.0.co;2-p.CrossRefPubMed

Imai K, Matsuyama S, Miyake S, Suga K, Nakachi K. Natural cytotoxic activity of peripheral-blood lymphocytes and cancer incidence: an 11-year follow-up study of a general population. Lancet. 2000;356(9244):1795-9. https://doi.org/10.1016/s0140-6736(00)03231-1.CrossRefPubMed

Koo KC, Shim DH, Yang CM, et al. Reduction of the CD16 − CD56bright NK cell subset precedes NK cell dysfunction in prostate cancer. PLoS One. 2013;8(11):e78049. https://doi.org/10.1371/journal.pone.0078049.CrossRefPubMedPubMedCentral

Pasero C, Gravis G, Granjeaud S, et al. Highly effective NK cells are associated with good prognosis in patients with metastatic prostate cancer. Oncotarget. 2015;6(16). https://doi.org/10.18632/oncotarget.3965.

Joseph J, Seervi M, Sobhan PK, Retnabai ST. High throughput ratio imaging to profile caspase activity: potential application in multiparameter high content apoptosis analysis and drug screening. PLoS One. 2011;6(5):e20114. https://doi.org/10.1371/journal.pone.0020114.CrossRefPubMedPubMedCentral

Tai LH, Zhang J, Scott KJ, et al. Perioperative influenza vaccination reduces postoperative metastatic disease by reversing surgery-induced dysfunction in natural killer cells. Clin Cancer Res. 2013;19(18):5104–15. https://doi.org/10.1158/1078-0432.ccr-13-0246.CrossRefPubMed

Benish M, Bartal I, Goldfarb Y, et al. Perioperative use of β-blockers and COX-2 inhibitors may improve immune competence and reduce the risk of tumor metastasis. Ann Surg Oncol. 2008;15(7):2042–52. https://doi.org/10.1245/s10434-008-9890-5.CrossRefPubMed

10.

Goldfarb Y, Sorski L, Benish M, Levi B, Melamed R, Ben-Eliyahu S. Improving postoperative immune status and resistance to cancer metastasis. Ann Surg. 2011;253(4):798–810. https://doi.org/10.1097/sla.0b013e318211d7b5.CrossRefPubMed

11.

Coffey JC, Wang JH, Smith MJF, Bouchier-Hayes D, Cotter TG, Redmond HP. Excisional surgery for cancer cure: therapy at a cost. Lancet Oncol. 2003;4(12):760–8. doi:S1470204503012828.CrossRefPubMed

12.

Pollock RE, Lotzová E, Stanford SD. Mechanism of surgical stress impairment of human perioperative natural killer cell cytotoxicity. Arch Surg. 1991;126(3):338. https://doi.org/10.1001/archsurg.1991.01410270082013.CrossRefPubMed

13.

Fujisawa T, Yamaguchi Y. Autologous tumor killing activity as a prognostic factor in primary resected nonsmall cell carcinoma of the lung. Cancer. 1997;79(3):474–81.CrossRefPubMed

14.

Klatte T, Ittenson A, Röhl F-W, Ecke M, Allhoff EP, McDougall I. Perioperative immunomodulation with interleukin-2 in patients with renal cell carcinoma: results of a controlled phase II trial. Br J Cancer. 2006;95(9):1167–73. https://doi.org/10.1038/sj.bjc.6603391.CrossRefPubMedPubMedCentral

15.

Auer RC. Trial of perioperative tadalafil and influenza vaccination in cancer patients undergoing major surgical resection of a primary abdominal malignancy (PERIOP-04). https://clinicaltrials.gov/ct2/show/NCT02998736.

16.

Shaashua L, Shabat-Simon M, Haldar R, 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. 2017;23(16):1–11. https://doi.org/10.1158/1078-0432.ccr-17-0152.CrossRef

17.

Cooper MA, Fehniger TA, Turner SC, et al. Human natural killer cells: a unique innate immunoregulatory role for the CD56brightsubset. Blood. 2001;97(10):3146–51. https://doi.org/10.1182/blood.v97.10.3146.CrossRefPubMed

18.

Michel T, Poli A, Cuapio A, et al. Human CD56 bright NK Cells: An Update. J Immunol. 2016;196(7):2923–31. https://doi.org/10.4049/jimmunol.1502570.CrossRefPubMed

19.

Lee S, Cha J, Kim I, et al. A high-throughput assay of NK cell activity in whole blood and its clinical application. Biochem Biophys Res Commun. 2014;445(3):584–90. https://doi.org/10.1016/j.bbrc.2014.02.040.CrossRefPubMed

20.

Menard C, Blay J-Y, Borg C, et al. Natural killer cell IFN- levels predict long-term survival with imatinib mesylate therapy in gastrointestinal stromal tumor-bearing patients. Cancer Res. 2009;69(8):3563–9. https://doi.org/10.1158/0008-5472.can-08-3807.CrossRefPubMed

21.

Lee J, Park KH, Ryu JH, et al. Natural killer cell activity for IFN-gamma production as a supportive diagnostic marker for gastric cancer. Oncotarget. 2017;8(41). https://doi.org/10.18632/oncotarget.19712.

22.

Derby EG, Reddy V, Nelson EL, et al. Correlation of human CD56 + cell cytotoxicity and IFN-y production. Cytokine. 2001;13(2):85-90. https://doi.org/10.1006/cyto.2000.0804.CrossRefPubMed

23.

Jobin G, Rodriguez-Suarez R, Betito K. Association between natural killer cell activity and colorectal cancer in high-risk subjects undergoing colonoscopy. Gastroenterology. 2017;153(4):980–7. https://doi.org/10.1053/j.gastro.2017.06.009.CrossRefPubMed

24.

Tai L-H, de Souza CT, Belanger S, et al. Preventing postoperative metastatic disease by inhibiting surgery-induced dysfunction in natural killer cells. Cancer Res. 2013;73(1):97–107. https://doi.org/10.1158/0008-5472.can-12-1993.CrossRefPubMed

25.

Bauernhofer T, Kuss I, Henderson B, Baum AS, Whiteside TL. Preferential apoptosis of CD56dim natural killer cell subset in patients with cancer. Eur J Immunol. 2003;33(1):119–24. https://doi.org/10.1002/immu.200390014.CrossRefPubMed

26.

Jones RO, Brittan M, Anderson NH, et al. Serial characterisation of monocyte and neutrophil function after lung resection. BMJ Open Respir Res. 2014;1(1):e000045. https://doi.org/10.1136/bmjresp-2014-000045.CrossRefPubMedPubMedCentral

27.

Yang J, Zhang L, Yu C, Yang X-F, Wang H. Monocyte and macrophage differentiation: circulation inflammatory monocyte as biomarker for inflammatory diseases. Biomark Res. 2014;2(1):1. https://doi.org/10.1186/2050-7771-2-1.CrossRefPubMedPubMedCentral

28.

Ertel W, Keel M, Neidhardt R, et al. Inhibition of the defense system stimulating interleukin-12 interferon-gamma pathway during critical illness. Blood. 1997;89(5):1612–20.PubMed

29.

Yadavalli GK, Chien JW, Wener KM, et al. Interleukin 12 and interferon-gamma synthetic deficiency is associated with dendritic cell cytopenia after cardiac surgery. Shock. 2005;24(1):26–33.CrossRefPubMed

30.

Reinhardt R, Pohlmann S, Kleinertz H, Hepner-Schefczyk M, Paul A, Flohé SB. Invasive surgery impairs the regulatory function of human CD56 bright natural killer cells in response to Staphylococcus aureus. suppression of interferon-γ synthesis. PLoS One. 2015;10(6):e0130155. https://doi.org/10.1371/journal.pone.0130155.CrossRefPubMed

31.

Kubica M, Guzik K, Koziel J, et al. A potential new pathway for Staphylococcus aureus dissemination: the silent survival of s. aureus phagocytosed by human monocyte-derived macrophages. PLoS One. 2008;3(1):e1409. https://doi.org/10.1371/journal.pone.0001409.CrossRefPubMedPubMedCentral

32.

Poli A, Michel T, Thérésine M, Andrès E, Hentges F, Zimmer J. CD56 bright natural killer (NK) cells: an important NK cell subset. Immunology. 2009;126(4):458–65. https://doi.org/10.1111/j.1365-2567.2008.03027.x.CrossRefPubMedPubMedCentral

33.

Jupelli M, Selby DM, Guentzel MN, et al. The contribution of interleukin-12/interferon-γ axis in protection against neonatal pulmonary Chlamydia muridarum challenge. J Interf Cytokine Res. 2010;30(6):407–15. https://doi.org/10.1089/jir.2009.0083.CrossRef

34.

Ramirez-Alejo N, Santos-Argumedo L. Innate defects of the IL-12/IFN-γ axis in susceptibility to infections by mycobacteria and salmonella. J Interf Cytokine Res. 2014;34(5):307–17. https://doi.org/10.1089/jir.2013.0050.CrossRef

35.

Ramirez MF, Ai D, Bauer M, et al. Innate immune function after breast, lung, and colorectal cancer surgery. J Surg Res. 2015;194(1):185–93. https://doi.org/10.1016/j.jss.2014.10.030.CrossRefPubMed

36.

Seth R, Tai L-H, Falls T, 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. 2013;258(1):158–68. https://doi.org/10.1097/sla.0b013e31826fcbdb.CrossRefPubMed

37.

Tai LH, Alkayyal AA, Leslie AL, et al. Phosphodiesterase-5 inhibition reduces postoperative metastatic disease by targeting surgery-induced myeloid derived suppressor cell-dependent inhibition of natural killer cell cytotoxicity. Oncoimmunology. 2018;7(6). https://doi.org/10.1080/2162402x.2018.1431082.CrossRefPubMedPubMedCentral

38.

Delogu G, Moretti S, Antonucci A, et al. Apoptosis and surgical trauma: dysregulated expression of death and survival factors on peripheral lymphocytes. Arch Surg. 2000;135(10):1141–7. https://doi.org/10.1001/archsurg.135.10.1141.CrossRefPubMed

39.

Ishikawa M, Nishioka M, Hanaki N, et al. Perioperative immune responses in cancer patients undergoing digestive surgeries. World J Surg Oncol. 2009;7(1):7. https://doi.org/10.1186/1477-7819-7-7.CrossRefPubMedPubMedCentral

40.

Ananth A, Tai L-H, Lansdell C, et al. Surgical stress abrogates Preexisting protective T cell mediated anti-tumor immunity leading to postoperative cancer recurrence (correction). PLoS One. 2016;11(5):e0155947. https://doi.org/10.1371/journal.pone.0155947.CrossRefPubMedPubMedCentral

41.

Wirsdörfer F, Bangen JM, Pastille E, Hansen W, Flohé SB. Breaking the co-operation between bystander T-cells and natural killer cells prevents the development of immunosuppression after traumatic skeletal muscle injury in mice. Clin Sci. 2015;128(11):825–38. https://doi.org/10.1042/cs20140835.CrossRef

42.

Solana R, Alonso MC, Peña J. Natural killer cells in healthy aging. Exp Gerontol. 1999;34(3):435–43. https://doi.org/10.1016/s0531-5565(99)00008-x.CrossRefPubMed

43.

Lee DH, Kim M, Kim M, et al. Age-dependent alterations in serum cytokines, peripheral blood mononuclear cell cytokine production, natural killer cell activity, and prostaglandin F2α. Immunol Res. 2017;65(5):1009–16. https://doi.org/10.1007/s12026-017-8940-0.CrossRefPubMed

44.

Levy BT, Bay C, Xu Y, et al. Test characteristics of faecal immunochemical tests (FIT) compared with optical colonoscopy. J Med Screen. 2014;21(3):133–43. https://doi.org/10.1177/0969141314541109.CrossRefPubMedPubMedCentral

45.

Gotlieb N, Rosenne E, Matzner P, Shaashua L, Sorski L, Ben-Eliyahu S. The misleading nature of in vitro and ex vivo findings in studying the impact of stress hormones on NK cell cytotoxicity. Brain Behav Immun. 2015;45:277–86. https://doi.org/10.1016/j.bbi.2014.12.020.CrossRefPubMed

46.

Bücklein V, Adunka T, Mendler AN, et al. Progressive natural killer cell dysfunction associated with alterations in subset proportions and receptor expression in soft-tissue sarcoma patients. Oncoimmunology. 2016;5(7):e1178421. https://doi.org/10.1080/2162402x.2016.1178421.CrossRefPubMedPubMedCentral

47.

MacFarlane AW, Jillab M, Smith MR, et al. NK cell dysfunction in chronic lymphocytic leukemia is associated with loss of the mature cells expressing inhibitory killer cell Ig-like receptors. Oncoimmunology. 2017:e1330235. https://doi.org/10.1080/2162402x.2017.1330235.

48.

Konjević G, Jurišić V, Spužić I. Association of NK cell dysfunction with changes in LDH characteristics of peripheral blood lymphocytes (PBL) in breast cancer patients. Breast Cancer Res Treat. 2001;66(3):255–63. https://doi.org/10.1023/a:1010602822483.CrossRefPubMed

49.

Velásquez JF, Ramírez MF, Ai DI, Lewis V, Cata JP. Impaired immune function in patients undergoing surgery for bone cancer. Anticancer Res. 2015;35(10):5461-6. http://www.ncbi.nlm.nih.gov/pubmed/26408709.

50.

Anfossi N, André P, Guia S, et al. Human NK cell education by inhibitory receptors for MHC class I. Immunity. 2006;25(2):331–42. https://doi.org/10.1016/j.immuni.2006.06.013.CrossRefPubMed

51.

De Maria A, Bozzano F, Cantoni C, Moretta L. Revisiting human natural killer cell subset function revealed cytolytic CD56dimCD16 + NK cells as rapid producers of abundant IFN- on activation. Proc Natl Acad Sci. 2011;108(2):728–32. https://doi.org/10.1073/pnas.1012356108.CrossRefPubMed

52.

Wang J, Yang L, Yu L, et al. Surgery-induced monocytic myeloid-derived suppressor cells expand regulatory T cells in lung cancer. Oncotarget. 2017;8(10):17050-8. https://doi.org/10.18632/oncotarget.14991.CrossRefPubMedPubMedCentral

53.

Wang J, Su X, Yang L, et al. The influence of myeloid-derived suppressor cells on angiogenesis and tumor growth after cancer surgery. Int J Cancer. 2016;138(11):2688–99. https://doi.org/10.1002/ijc.29998.CrossRefPubMed

54.

Thäle C, Kiderlen AF. Sources of interferon-gamma (IFN-γ) in early immune response to Listeria monocytogenes. Immunobiology. 2005;210(9):673–83. https://doi.org/10.1016/j.imbio.2005.07.003.CrossRefPubMed

55.

Auer RC. Perioperative immunonutrition in colorectal cancer patients undergoing abdominal surgery (PERIOP-02). https://clinicaltrials.gov/ct2/show/NCT02987296.

Title: Natural Killer Cell IFNγ Secretion is Profoundly Suppressed Following Colorectal Cancer Surgery
Authors: Leonard Angka, MSc
Andre B. Martel, MD
Marisa Kilgour, BSc
Ahwon Jeong, BSc
Manahil Sadiq, BSc
Christiano Tanese de Souza, DVet
Laura Baker, MD
Michael A. Kennedy, PhD
Natasha Kekre, MD, MPH
Rebecca C. Auer, MD, MSc
Publication date: 01-11-2018
Publisher: Springer International Publishing
Published in: Annals of Surgical Oncology / Issue 12/2018
Print ISSN: 1068-9265
Electronic ISSN: 1534-4681
DOI: https://doi.org/10.1245/s10434-018-6691-3

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Natural Killer Cell IFNγ Secretion is Profoundly Suppressed Following Colorectal Cancer Surgery

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 12/2018

Frozen Section for Detection of Lymph Nodes After Cervical Injection with Indocyanine Green (ICG) for Sentinel Lymph Node Technique in Endometrial Cancer Staging

Multidisciplinary Management of the Axilla in Patients with cT1-T2 N0 Breast Cancer Undergoing Primary Mastectomy: Results from a Prospective Single-Institution Series

CA19-9 on Postoperative Surveillance in Pancreatic Ductal Adenocarcinoma: Predicting Recurrence and Changing Prognosis over Time

Recurrence Risk Based on Pathologic Stage After Neoadjuvant Chemoradiotherapy in Esophageal Squamous Cell Carcinoma: Implications for Risk-Based Postoperative Surveillance Strategies

Optimal Cutoff Values of Skeletal Muscle Index to Define Sarcopenia for Prediction of Survival in Patients with Advanced Gastric Cancer

Questions About In-Breast Tumor Recurrence in Patients Treated with Breast-Conserving Therapy