Cancer Immunology, Immunotherapy

, Volume 64, Issue 11, pp 1383–1392 | Cite as

Surgical trauma induces postoperative T-cell dysfunction in lung cancer patients through the programmed death-1 pathway

  • Pingbo Xu
  • Ping Zhang
  • Zhirong Sun
  • Yun Wang
  • Jiawei Chen
  • Changhong Miao
Original Article


The programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1) pathway have been shown to be involved in tumor-induced and sepsis-induced immunosuppression. However, whether this pathway is involved in the surgery-induced dysfunction of T lymphocytes is not known. Here, we analyzed expression of PD-1 and PD-L1 on human peripheral mononuclear cells during the perioperative period. We found that surgery increased PD-1/PD-L1 expression on immune cells, which was correlated with the severity of surgical trauma. The count of T lymphocytes and natural killer cells reduced after surgery, probably due to the increased activity of caspase-3. Caspase-3 level was positively correlated with PD-1 expression. Profile of perioperative cytokines and hormones in plasma showed a significantly increased level of interferon-α, as well as various inflammatory cytokines and stress hormones. In ex vivo experiments, administration of anti-PD-1 antibody significantly ameliorated T-cell proliferation and partially reversed the T-cell apoptosis induced by surgical trauma. We provide evidences that surgical trauma can induce immunosuppression through the PD-1/PD-L1 pathway. This pathway could be a target for preventing postoperative cellular immunosuppression.


PD-1/PD-L1 Surgery Immunosuppression Lung cancer 



Dendritic cells


Interferon alpha




Natural killer


Peripheral blood monocyte cells


Programmed death-1


Programmed death ligand-1


Programmed death ligand-2


Prostaglandin E2


Postoperative day


Tumor necrosis factor alpha



Funding was received from National Natural Science Foundation of China (NSFC 81471852) and Shanghai Natural Science Foundation (KW 1307, KW142R1407500).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

262_2015_1740_MOESM1_ESM.pdf (135 kb)
Supplementary material 1 (PDF 135 kb)


  1. 1.
    Darby S, McGale P, Correa C et al (2011) Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10,801 women in 17 randomised trials. Lancet 378:1707–1716. doi: 10.1016/S0140-6736(11)61629-2 CrossRefPubMedGoogle Scholar
  2. 2.
    Tsuchiya Y, Sawada S, Yoshioka I et al (2003) Increased surgical stress promotes tumor metastasis. Surgery 133:547–555. doi: 10.1067/msy.2003.141 CrossRefPubMedGoogle Scholar
  3. 3.
    Glasner A, Avraham R, Rosenne E et al (2010) Improving survival rates in two models of spontaneous postoperative metastasis in mice by combined administration of a beta-adrenergic antagonist and a cyclooxygenase-2 inhibitor. J Immunol 184:2449–2457. doi: 10.4049/jimmunol.0903301 CrossRefPubMedGoogle Scholar
  4. 4.
    Yamaguchi K, Takagi Y, Aoki S et al (2000) Significant detection of circulating cancer cells in the blood by reverse transcriptase–polymerase chain reaction during colorectal cancer resection. Ann Surg 232:58–65PubMedCentralCrossRefPubMedGoogle Scholar
  5. 5.
    Melamed R, Bar-Yosef S, Shakhar G et al (2003) 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 97:1331–1339CrossRefPubMedGoogle Scholar
  6. 6.
    Shavit Y, Ben-Eliyahu S, Zeidel A, Beilin B (2004) Effects of fentanyl on natural killer cell activity and on resistance to tumor metastasis in rats. Dose and timing study. Neuroimmunomodulation 11:255–260. doi: 10.1159/000078444 CrossRefPubMedGoogle Scholar
  7. 7.
    Mokbel K, Choy C, Engledow A (2000) The effect of surgical wounding on tumour development. Eur J Surg Oncol 26:195. doi: 10.1053/ejso.1999.0771 CrossRefPubMedGoogle Scholar
  8. 8.
    Lutgendorf SK, Cole S, Costanzo E et al (2003) Stress-related mediators stimulate vascular endothelial growth factor secretion by two ovarian cancer cell lines. Clin Cancer Res 9:4514–4521PubMedGoogle Scholar
  9. 9.
    Shakhar G, Ben-Eliyahu S (2003) Potential prophylactic measures against postoperative immunosuppression: could they reduce recurrence rates in oncological patients? Ann Surg Oncol 10:972–992CrossRefPubMedGoogle Scholar
  10. 10.
    Tai LH, de Souza CT, Belanger S et al (2013) Preventing postoperative metastatic disease by inhibiting surgery-induced dysfunction in natural killer cells. Cancer Res 73:97–107. doi: 10.1158/0008-5472.CAN-12-1993 CrossRefPubMedGoogle Scholar
  11. 11.
    Grivennikov SI, Greten FR, Karin M (2010) Immunity, inflammation, and cancer. Cell 140:883–899. doi: 10.1016/j.cell.2010.01.025 PubMedCentralCrossRefPubMedGoogle Scholar
  12. 12.
    Zamarron BF, Chen W (2011) Dual roles of immune cells and their factors in cancer development and progression. Int J Biol Sci 7:651–658PubMedCentralCrossRefPubMedGoogle Scholar
  13. 13.
    Levi B, Benish M, Goldfarb Y et al (2011) Continuous stress disrupts immunostimulatory effects of IL-12. Brain Behav Immun 25:727–735. doi: 10.1016/j.bbi.2011.01.014 PubMedCentralCrossRefPubMedGoogle Scholar
  14. 14.
    Ostrand-Rosenberg S, Sinha P (2009) Myeloid-derived suppressor cells: linking inflammation and cancer. J Immunol 182:4499–4506. doi: 10.4049/jimmunol.0802740 PubMedCentralCrossRefPubMedGoogle Scholar
  15. 15.
    Gottschalk A, Sharma S, Ford J et al (2010) Review article: the role of the perioperative period in recurrence after cancer surgery. Anesth Analg 110:1636–1643. doi: 10.1213/ANE.0b013e3181de0ab6 CrossRefPubMedGoogle Scholar
  16. 16.
    Hogan BV, Peter MB, Shenoy HG et al (2011) Surgery induced immunosuppression. Surgeon 9:38–43. doi: 10.1016/j.surge.2010.07.011 CrossRefPubMedGoogle Scholar
  17. 17.
    Eltzschig HK, Carmeliet P (2011) Hypoxia and inflammation. N Engl J Med 364:656–665. doi: 10.1056/NEJMra0910283 PubMedCentralCrossRefPubMedGoogle Scholar
  18. 18.
    Qadan M, Gardner SA, Vitale DS et al (2009) Hypothermia and surgery: immunologic mechanisms for current practice. Ann Surg 250:134–140. doi: 10.1097/SLA.0b013e3181ad85f7 PubMedCentralCrossRefPubMedGoogle Scholar
  19. 19.
    Bernard A, Meier C, Ward M et al (2010) Packed red blood cells suppress T-cell proliferation through a process involving cell–cell contact. J Trauma 69:320–329. doi: 10.1097/TA.0b013e3181e401f0 CrossRefPubMedGoogle Scholar
  20. 20.
    Borner C, Warnick B, Smida M et al (2009) Mechanisms of opioid-mediated inhibition of human T cell receptor signaling. J Immunol 183:882–889. doi: 10.4049/jimmunol.0802763 CrossRefPubMedGoogle Scholar
  21. 21.
    Al-Hasani R, Bruchas MR (2011) Molecular mechanisms of opioid receptor-dependent signaling and behavior. Anesthesiology 115:1363–1381. doi: 10.1097/ALN.0b013e318238bba6 PubMedCentralPubMedGoogle Scholar
  22. 22.
    Walz CR, Zedler S, Schneider CP et al (2009) The potential role of T-cells and their interaction with antigen-presenting cells in mediating immunosuppression following trauma-hemorrhage. Innate Immun 15:233–241. doi: 10.1177/1753425909104679 CrossRefPubMedGoogle Scholar
  23. 23.
    Albertsmeier M, Quaiser D, von Dossow-Hanfstingl V et al (2015) Major surgical trauma differentially affects T-cells and APC. Innate Immun 21:55–64. doi: 10.1177/1753425913516659 CrossRefPubMedGoogle Scholar
  24. 24.
    Topalian SL, Drake CG, Pardoll DM (2012) Targeting the PD-1/B7-H1(PD-L1) pathway to activate anti-tumor immunity. Curr Opin Immunol 24:207–212. doi: 10.1016/j.coi.2011.12.009 PubMedCentralCrossRefPubMedGoogle Scholar
  25. 25.
    Arai Y, Saito H, Ikeguchi M (2012) Upregulation of TIM-3 and PD-1 on CD4+ and CD8+ T cells associated with dysfunction of cell-mediated immunity after colorectal cancer operation. Yonago Acta Med 55:1–9PubMedCentralPubMedGoogle Scholar
  26. 26.
    Kinter AL, Godbout EJ, McNally JP et al (2008) The common gamma-chain cytokines IL-2, IL-7, IL-15, and IL-21 induce the expression of programmed death-1 and its ligands. J Immunol 181:6738–6746CrossRefPubMedGoogle Scholar
  27. 27.
    Terawaki S, Chikuma S, Shibayama S et al (2011) IFN-α directly promotes programmed cell death-1 transcription and limits the duration of T cell-mediated immunity. J Immunol 186:2772–2779. doi: 10.4049/jimmunol.1003208 CrossRefPubMedGoogle Scholar
  28. 28.
    Topalian SL, Hodi FS, Brahmer JR et al (2012) Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366:2443–2454. doi: 10.1056/NEJMoa1200690 PubMedCentralCrossRefPubMedGoogle Scholar
  29. 29.
    Fife BT, Pauken KE, Eagar TN et al (2009) Interactions between PD-1 and PD-L1 promote tolerance by blocking the TCR-induced stop signal. Nat Immunol 10:1185–1192. doi: 10.1038/ni.1790 PubMedCentralCrossRefPubMedGoogle Scholar
  30. 30.
    Brahmer JR, Drake CG, Wollner I et al (2010) Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol 28:3167–3175. doi: 10.1200/JCO.2009.26.7609 CrossRefPubMedGoogle Scholar
  31. 31.
    Curran MA, Montalvo W, Yagita H, Allison JP (2010) PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc Natl Acad Sci USA 107:4275–4280. doi: 10.1073/pnas.0915174107 PubMedCentralCrossRefPubMedGoogle Scholar
  32. 32.
    Duraiswamy J, Kaluza KM, Freeman GJ, Coukos G (2013) Dual blockade of PD-1 and CTLA-4 combined with tumor vaccine effectively restores T-cell rejection function in tumors. Cancer Res 73:3591–3603. doi: 10.1158/0008-5472.CAN-12-4100 PubMedCentralCrossRefPubMedGoogle Scholar
  33. 33.
    Brahmer JR, Tykodi SS, Chow LQ et al (2012) Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 366:2455–2465. doi: 10.1056/NEJMoa1200694 PubMedCentralCrossRefPubMedGoogle Scholar
  34. 34.
    Bellone S, Centritto F, Black J et al (2015) Polymerase epsilon (POLE) ultra-mutated tumors induce robust tumor-specific CD4+ T cell responses in endometrial cancer patients. Gynecol Oncol 138(1):11–17. doi: 10.1016/j.ygyno.2015.04.027 CrossRefPubMedGoogle Scholar
  35. 35.
    Eng JW, Kokolus KM, Reed CB et al (2014) A nervous tumor microenvironment: the impact of adrenergic stress on cancer cells, immunosuppression, and immunotherapeutic response. Cancer Immunol Immunother 63:1115–1128. doi: 10.1007/s00262-014-1617-9 CrossRefPubMedGoogle Scholar
  36. 36.
    Brahmamdam P, Inoue S, Unsinger J et al (2010) Delayed administration of anti-PD-1 antibody reverses immune dysfunction and improves survival during sepsis. J Leukoc Biol 88:233–240. doi: 10.1189/jlb.0110037 CrossRefPubMedGoogle Scholar
  37. 37.
    Zhang Y, Zhou Y, Lou J et al (2010) PD-L1 blockade improves survival in experimental sepsis by inhibiting lymphocyte apoptosis and reversing monocyte dysfunction. Crit Care 14:R220. doi: 10.1186/cc9354 PubMedCentralCrossRefPubMedGoogle Scholar
  38. 38.
    Zhang Y, Li J, Lou J et al (2011) Upregulation of programmed death-1 on T cells and programmed death ligand-1 on monocytes in septic shock patients. Crit Care 15:R70. doi: 10.1186/cc10059 PubMedCentralCrossRefPubMedGoogle Scholar
  39. 39.
    MacFarlane AW IV, Jillab M, Plimack ER et al (2014) PD-1 expression on peripheral blood cells increases with stage in renal cell carcinoma patients and is rapidly reduced after surgical tumor resection. Cancer Immunol Res 2:320–331. doi: 10.1158/2326-6066.CIR-13-0133 PubMedCentralCrossRefPubMedGoogle Scholar
  40. 40.
    Hotchkiss RS, Chang KC, Swanson PE et al (2000) Caspase inhibitors improve survival in sepsis: a critical role of the lymphocyte. Nat Immunol 1(6):496–501CrossRefPubMedGoogle Scholar
  41. 41.
    Hotchkiss RS, Tinsley KW, Swanson PE et al (1999) Prevention of lymphocyte cell death in sepsis improves survival in mice. Proc Natl Acad Sci USA 96(25):14541–14546PubMedCentralCrossRefPubMedGoogle Scholar
  42. 42.
    Unsinger J, McGlynn M, Kasten KR et al (2010) IL-7 promotes T cell viability, trafficking, and functionality and improves survival in sepsis. J Immunol 184(7):3768–7379. doi: 10.4049/jimmunol.0903151 PubMedCentralCrossRefPubMedGoogle Scholar
  43. 43.
    Muszynski JA, Nofziger R, Greathouse K et al (2014) Early adaptive immune suppression in children with septic shock: a prospective observational study. Crit Care 18(4):R145. doi: 10.1186/cc13980 PubMedCentralCrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Pingbo Xu
    • 1
  • Ping Zhang
    • 2
  • Zhirong Sun
    • 1
  • Yun Wang
    • 1
  • Jiawei Chen
    • 1
  • Changhong Miao
    • 1
  1. 1.Department of AnesthesiologyFudan University Shanghai Cancer CenterShanghaiPeople’s Republic of China
  2. 2.Cancer InstituteFudan University Shanghai Cancer CenterShanghaiPeople’s Republic of China

Personalised recommendations