Skip to main content
Erschienen in: Surgery Today 11/2016

22.01.2016 | Original Article

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

verfasst von: Shuichi Takano, Hiroaki Saito, Masahide Ikeguchi

Erschienen in: Surgery Today | Ausgabe 11/2016

Einloggen, um Zugang zu erhalten

Abstract

Purpose

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.

Methods

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.

Results

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.

Conclusion

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.
Literatur
1.
Zurück zum Zitat Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. 2005;55:74–108.CrossRefPubMed Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. 2005;55:74–108.CrossRefPubMed
2.
Zurück zum Zitat 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.CrossRefPubMed 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.CrossRefPubMed
3.
Zurück zum Zitat 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.CrossRefPubMed 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.CrossRefPubMed
4.
Zurück zum Zitat Chen L. Co-inhibitory molecules of the B7-CD28 family in the control of T-cell immunity. Nat Rev Immunol. 2004;4:336–47.CrossRefPubMed Chen L. Co-inhibitory molecules of the B7-CD28 family in the control of T-cell immunity. Nat Rev Immunol. 2004;4:336–47.CrossRefPubMed
5.
Zurück zum Zitat Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisited. Annu Rev Immunol. 2005;23:515–48.CrossRefPubMed Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisited. Annu Rev Immunol. 2005;23:515–48.CrossRefPubMed
6.
Zurück zum Zitat 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.CrossRefPubMed 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.CrossRefPubMed
7.
Zurück zum Zitat 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
8.
Zurück zum Zitat 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.CrossRefPubMed 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.CrossRefPubMed
9.
Zurück zum Zitat 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
10.
Zurück zum Zitat 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.CrossRefPubMed 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.CrossRefPubMed
11.
Zurück zum Zitat 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.CrossRefPubMed 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.CrossRefPubMed
12.
Zurück zum Zitat 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.CrossRefPubMed 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.CrossRefPubMed
13.
Zurück zum Zitat 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.CrossRefPubMed 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.CrossRefPubMed
14.
Zurück zum Zitat 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
15.
Zurück zum Zitat 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
16.
Zurück zum Zitat 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.CrossRefPubMed 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.CrossRefPubMed
17.
Zurück zum Zitat 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.CrossRefPubMed 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.CrossRefPubMed
18.
Zurück zum Zitat Association Japanese Gastric Cancer. Japanese classification of gastric carcinoma: 2nd English Edition. Gastric Cancer. 1998;1:10–24.CrossRef Association Japanese Gastric Cancer. Japanese classification of gastric carcinoma: 2nd English Edition. Gastric Cancer. 1998;1:10–24.CrossRef
19.
Zurück zum Zitat 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.CrossRefPubMed 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.CrossRefPubMed
20.
Zurück zum Zitat 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.CrossRefPubMed 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.CrossRefPubMed
21.
Zurück zum Zitat 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.CrossRefPubMed 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.CrossRefPubMed
22.
Zurück zum Zitat 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.CrossRefPubMed 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.CrossRefPubMed
23.
Zurück zum Zitat 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.CrossRefPubMed 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.CrossRefPubMed
24.
Zurück zum Zitat 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
25.
Zurück zum Zitat Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol. 2008;26:677–704.CrossRefPubMed Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol. 2008;26:677–704.CrossRefPubMed
26.
Zurück zum Zitat 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
27.
Zurück zum Zitat 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.CrossRefPubMed 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.CrossRefPubMed
28.
Zurück zum Zitat 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.CrossRefPubMed 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.CrossRefPubMed
29.
Zurück zum Zitat Melero I, Hervas-Stubbs S, Glennie M, Pardoll DM, Chen L. Immunostimulatory monoclonal antibodies for cancer therapy. Nat Rev Cancer. 2007;7:95–106.CrossRefPubMed Melero I, Hervas-Stubbs S, Glennie M, Pardoll DM, Chen L. Immunostimulatory monoclonal antibodies for cancer therapy. Nat Rev Cancer. 2007;7:95–106.CrossRefPubMed
30.
Zurück zum Zitat 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
31.
Zurück zum Zitat 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.CrossRefPubMed 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.CrossRefPubMed
32.
Zurück zum Zitat 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.CrossRefPubMed 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.CrossRefPubMed
33.
Zurück zum Zitat 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
34.
Zurück zum Zitat 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.CrossRefPubMed 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.CrossRefPubMed
Metadaten
Titel
An increased number of PD-1+ and Tim-3+ CD8+ T cells is involved in immune evasion in gastric cancer
verfasst von
Shuichi Takano
Hiroaki Saito
Masahide Ikeguchi
Publikationsdatum
22.01.2016
Verlag
Springer Japan
Erschienen in
Surgery Today / Ausgabe 11/2016
Print ISSN: 0941-1291
Elektronische ISSN: 1436-2813
DOI
https://doi.org/10.1007/s00595-016-1305-9

Weitere Artikel der Ausgabe 11/2016

Surgery Today 11/2016 Zur Ausgabe

Leitlinien kompakt für die Allgemeinmedizin

Mit medbee Pocketcards sicher entscheiden.

Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag

Facharzt-Training Allgemeinmedizin

Die ideale Vorbereitung zur anstehenden Prüfung mit den ersten 24 von 100 klinischen Fallbeispielen verschiedener Themenfelder

Mehr erfahren

Update Allgemeinmedizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.