Surgery Today

, Volume 46, Issue 11, pp 1341–1347 | Cite as

An increased number of PD-1+ and Tim-3+ CD8+ T cells is involved in immune evasion in gastric cancer

  • Shuichi Takano
  • Hiroaki SaitoEmail author
  • Masahide Ikeguchi
Original Article



Co-signaling molecules play an important role in T cells. This study was designed to investigate PD-1 and Tim-3 expression on T cells and the relationships between PD-1 and Tim-3 expression and immune evasion in patients with gastric cancer.


Using multicolor flow cytometry, we analyzed PD-1 and Tim-3 expression on CD8+ T cells obtained from peripheral blood mononuclear cells (PBMCs) and gastric cancer tissue.


Significantly more PD-1+ and Tim-3+ CD8+ T cells in peripheral blood were found in gastric cancer patients than in healthy controls. PD-1+ CD8+ T cells were significantly correlated with Tim-3+ CD8+ T cells in peripheral blood from the gastric cancer patients (r = 0.29, p = 0.036). Furthermore, significantly greater numbers of PD-1+ and Tim-3+ CD8+ T cells were seen in the gastric cancer tissue samples than in the PBMCs. CD8+ T cells positive for both PD-1 and Tim-3 produced significantly less IFN-gamma than cells negative for both and cells positive for PD-1 and negative for Tim-3.


An increased number of PD-1+ and Tim-3+ CD8+ T cells is closely related to impaired function of CD8+ T cells in gastric cancer patients.


Gastric cancer PD-1 T cell Tim-3 



We thank Ms. Miyauchi and Dr. Nakayama (Division of Functional Genomics, Research Center for Bioscience and Technology, Tottori University) for their help with cell sorting. This work was supported by JSPS KAKENHI Grant Number 23501285.

Compliance with ethical standards

Conflict of interest

We report no proprietary or commercial interests in any product mentioned or concept discussed in this article.


  1. 1.
    Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. 2005;55:74–108.CrossRefPubMedGoogle Scholar
  2. 2.
    Inoue H, Mori M, Honda M, Li J, Shibuta K, Mimori K, et al. The expression of tumor-rejection antigen “MAGE” genes in human gastric carcinoma. Gastroenterology. 1995;109:1522–5.CrossRefPubMedGoogle Scholar
  3. 3.
    Hoshino T, Seki N, Kikuchi M, Kuramoto T, Iwamoto O, Kodama I, et al. HLA class-I-restricted and tumor-specific CTL in tumor-infiltrating lymphocytes of patients with gastric cancer. Int J Cancer. 1997;70:631–8.CrossRefPubMedGoogle Scholar
  4. 4.
    Chen L. Co-inhibitory molecules of the B7-CD28 family in the control of T-cell immunity. Nat Rev Immunol. 2004;4:336–47.CrossRefPubMedGoogle Scholar
  5. 5.
    Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisited. Annu Rev Immunol. 2005;23:515–48.CrossRefPubMedGoogle Scholar
  6. 6.
    Sharpe AH, Wherry EJ, Ahmed R, Freeman GJ. The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection. Nat Immunol. 2007;8:239–45.CrossRefPubMedGoogle Scholar
  7. 7.
    Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med. 2000;192:1027–34.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Dong H, Zhu G, Tamada K, Chen L. B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat Med. 1999;5:1365–9.CrossRefPubMedGoogle Scholar
  9. 9.
    Tseng SY, Otsuji M, Gorski K, Huang X, Slansky JE, Pai SI, et al. B7-DC, a new dendritic cell molecule with potent costimulatory properties for T cells. J Exp Med. 2001;193:839–46.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Latchman Y, Wood CR, Chernova T, Chaudhary D, Borde M, Chernova I, et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol. 2001;2:261–8.CrossRefPubMedGoogle Scholar
  11. 11.
    Keir ME, Freeman GJ, Sharpe AH. PD-1 regulates self-reactive CD8+ T cell responses to antigen in lymph nodes and tissues. J Immunol. 2007;179:5064–70.CrossRefPubMedGoogle Scholar
  12. 12.
    Nishimura H, Okazaki T, Tanaka Y, Nakatani K, Hara M, Matsumori A, et al. Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science. 2001;291:319–22.CrossRefPubMedGoogle Scholar
  13. 13.
    Nishimura H, Nose M, Hiai H, Minato N, Honjo T. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity. 1999;11:141–51.CrossRefPubMedGoogle Scholar
  14. 14.
    Matsuzaki J, Gnjatic S, Mhawech-Fauceglia P, Beck A, Miller A, Tsuji T, et al. Tumor-infiltrating NY-ESO-1-specific CD8+ T cells are negatively regulated by LAG-3 and PD-1 in human ovarian cancer. Proc Natl Acad Sci USA. 2010;107:7875–80.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Jones RB, Ndhlovu LC, Barbour JD, Sheth PM, Jha AR, Long BR, et al. Tim-3 expression defines a novel population of dysfunctional T cells with highly elevated frequencies in progressive HIV-1 infection. J Exp Med. 2008;205:2763–79.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Saito H, Yamada Y, Takaya S, Osaki T, Ikeguchi M. Clinical relevance of the number of interleukin-17-producing CD8+ T cells in patients with gastric cancer. Surg Today. 2015;45:1429–35.CrossRefPubMedGoogle Scholar
  17. 17.
    Osaki T, Saito H, Yoshikawa T, Matsumoto S, Tatebe S, Tsujitani S, et al. Decreased NKG2D expression on CD8+ T cell is involved in immune evasion in patients with gastric cancer. Clin Cancer Res. 2007;13:382–7.CrossRefPubMedGoogle Scholar
  18. 18.
    Association Japanese Gastric Cancer. Japanese classification of gastric carcinoma: 2nd English Edition. Gastric Cancer. 1998;1:10–24.CrossRefGoogle Scholar
  19. 19.
    Chemnitz JM, Parry RV, Nichols KE, June CH, Riley JL. SHP-1 and SHP-2 associate with immunoreceptor tyrosine-based switch motif of programmed death 1 upon primary human T cell stimulation, but only receptor ligation prevents T cell activation. J Immunol. 2004;173:945–54.CrossRefPubMedGoogle Scholar
  20. 20.
    Monney L, Sabatos CA, Gaglia JL, Ryu A, Waldner H, Chernova T, et al. Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease. Nature. 2002;415:536–41.CrossRefPubMedGoogle Scholar
  21. 21.
    Sabatos CA, Chakravarti S, Cha E, Schubart A, Sanchez-Fueyo A, Zheng XX, et al. Interaction of Tim-3 and Tim-3 ligand regulates T helper type 1 responses and induction of peripheral tolerance. Nat Immunol. 2003;4:1102–10.CrossRefPubMedGoogle Scholar
  22. 22.
    Sanchez-Fueyo A, Tian J, Picarella D, Domenig C, Zheng XX, Sabatos CA, et al. Tim-3 inhibits T helper type 1-mediated auto- and alloimmune responses and promotes immunological tolerance. Nat Immunol. 2003;4:1093–101.CrossRefPubMedGoogle Scholar
  23. 23.
    Zhu C, Anderson AC, Schubart A, Xiong H, Imitola J, Khoury SJ, et al. The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity. Nat Immunol. 2005;6:1245–52.CrossRefPubMedGoogle Scholar
  24. 24.
    Koguchi K, Anderson DE, Yang L, O’Connor KC, Kuchroo VK, Hafler DA. Dysregulated T cell expression of TIM3 in multiple sclerosis. J Exp Med. 2006;203:1413–8.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol. 2008;26:677–704.CrossRefPubMedGoogle Scholar
  26. 26.
    Golden-Mason L, Palmer BE, Kassam N, Townshend-Bulson L, Livingston S, McMahon BJ, et al. Negative immune regulator Tim-3 is overexpressed on T cells in hepatitis C virus infection and its blockade rescues dysfunctional CD4+ and CD8+ T cells. J Virol. 2009;83:9122–30.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Ikeguchi M, Hatada T, Yamamoto M, Miyake T, Matsunaga T, Fukumoto Y, et al. Serum interleukin-6 and -10 levels in patients with gastric cancer. Gastric Cancer. 2009;12:95–100.CrossRefPubMedGoogle Scholar
  28. 28.
    Sakamoto T, Saito H, Tatebe S, Tsujitani S, Ozaki M, Ito H, et al. Interleukin-10 expression significantly correlates with minor CD8+ T-cell infiltration and high microvessel density in patients with gastric cancer. Int J Cancer. 2006;118:1909–14.CrossRefPubMedGoogle Scholar
  29. 29.
    Melero I, Hervas-Stubbs S, Glennie M, Pardoll DM, Chen L. Immunostimulatory monoclonal antibodies for cancer therapy. Nat Rev Cancer. 2007;7:95–106.CrossRefPubMedGoogle Scholar
  30. 30.
    Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711–23.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015;372:320–30.CrossRefPubMedGoogle Scholar
  32. 32.
    Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, et al. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. 2015;372:2521–32.CrossRefPubMedGoogle Scholar
  33. 33.
    Brahmer J, Reckamp KL, Baas P, Crino L, Eberhardt WE, Poddubskaya E, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med. 2015;373:123–35.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Postow MA, Chesney J, Pavlick AC, Robert C, Grossmann K, McDermott D, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015;372:2006–17.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Japan 2016

Authors and Affiliations

  • Shuichi Takano
    • 1
  • Hiroaki Saito
    • 1
    Email author
  • Masahide Ikeguchi
    • 1
  1. 1.Division of Surgical Oncology, Department of SurgeryTottori University School of MedicineYonagoJapan

Personalised recommendations