Skip to main content

Advertisement

SpringerLink
Log in

Increased prevalence of tumor-infiltrating regulatory T cells is closely related to their lower sensitivity to H2O2-induced apoptosis in gastric and esophageal cancer

  • Original article
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Purpose and experimental design

Although an increase in regulatory T cells (Tregs) is observed in tumor microenvironments, the underlying mechanism is not fully clarified. Since it was suggested that Tregs showed a lower sensitivity toward oxidative stress in comparison with conventional T cells, in the present study, we investigated the H2O2 production and apoptosis of Tregs in gastric and esophageal cancer tissues, employing flow cytometric analysis using fresh samples (n = 93) and immunohistochemical analysis (n = 203).

Results

The increased tumor-infiltrating Tregs coexisted with elevated H2O2 production according to disease progression. The grade of apoptosis in Tregs was less pronounced than that in conventional T cells, and there was a positive correlation between H2O2 production and the grade of apoptosis in conventional T cells, while there was no correlation between H2O2 production and the grade of apoptosis in Tregs. Moreover, Tregs were less sensitive to H2O2-induced apoptosis compared with conventional T cells in vitro.

Conclusions

We have demonstrated that the increased prevalence of tumor-infiltrating Tregs closely related to their lower sensitivity to H2O2-induced apoptosis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Sakaguchi S, Ono M, Setoguchi R, Yagi H, Hori S, Fehervari Z et al (2006) Foxp3+CD25+CD4+ natural regulatory T cells in dominant self-tolerance and autoimmune disease. Immunol Rev 212:8–27

    Article  PubMed  CAS  Google Scholar 

  2. Beyer M, Schultze JL (2006) Regulatory T cells in cancer. Blood 108:804–811

    Article  PubMed  CAS  Google Scholar 

  3. Ichihara F, Kono K, Takahashi A, Kawaida H, Sugai H, Fujii H (2003) Increased populations of regulatory T cells in peripheral blood and tumor-infiltrating lymphocytes in patients with gastric and esophageal cancers. Clin Cancer Res 9:4404–4408

    PubMed  Google Scholar 

  4. Siddiqui SA, Frigola X, Bonne-Annee S, Mercader M, Kuntz SM, Krambeck AE et al (2007) Tumor-infiltrating Foxp3−CD4+CD25+ T cells predict poor survival in renal cell carcinoma. Clin Cancer Res 13:2075–2081

    Article  PubMed  CAS  Google Scholar 

  5. Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P et al (2004) Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 10:942–949

    Article  PubMed  CAS  Google Scholar 

  6. Kono K, Kawaida H, Takahashi A, Sugai H, Mimura K, Miyagawa N et al (2006) CD4(+)CD25high regulatory T cells increase with tumor stage in patients with gastric and esophageal cancers. Cancer Immunol Immunother 55:1064–1071

    Article  PubMed  CAS  Google Scholar 

  7. Mizukami Y, Kono K, Kawaguchi Y, Akaike H, Kamimura K, Sugai H et al (2008) CCL17 and CCL22 chemokines within tumor microenvironment are related to accumulation of Foxp3+ regulatory T cells in gastric cancer. Int J Cancer 122:2286–2293

    Article  PubMed  CAS  Google Scholar 

  8. Maruyama T, Kono K, Izawa S, Mizukami Y, Kawaguchi Y, Mimura K et al (2010) CCL17 and CCL22 chemokines within tumor microenvironment are related to infiltration of regulatory T cells in esophageal squamous cell carcinoma. Dis Esophagus 23:422–429

    PubMed  CAS  Google Scholar 

  9. Niedbala W, Cai B, Liu H, Pitman N, Chang L, Liew FY (2007) Nitric oxide induces CD4+CD25+Foxp3− regulatory T cells from CD4+CD25 T cells via p53, IL-2, and OX40. Proc Natl Acad Sci USA 104:15478–15483

    Article  PubMed  CAS  Google Scholar 

  10. Bergmann C, Strauss L, Zeidler R, Lang S, Whiteside TL (2007) Expansion of human T regulatory type 1 cells in the microenvironment of cyclooxygenase 2 overexpressing head and neck squamous cell carcinoma. Cancer Res 67:8865–8873

    Article  PubMed  CAS  Google Scholar 

  11. Mougiakakos D, Johansson CC, Kiessling R (2009) Naturally occurring regulatory T cells show reduced sensitivity toward oxidative stress-induced cell death. Blood 113:3542–3545

    Article  PubMed  CAS  Google Scholar 

  12. Szatrowski TP, Nathan CF (1991) Production of large amounts of hydrogen peroxide by human tumor cells. Cancer Res 51:794–798

    PubMed  CAS  Google Scholar 

  13. Kusmartsev S, Nefedova Y, Yoder D, Gabrilovich DI (2004) Antigen-specific inhibition of CD8+ T cell response by immature myeloid cells in cancer is mediated by reactive oxygen species. J Immunol 172:989–999

    PubMed  CAS  Google Scholar 

  14. Kondo S, Toyokuni S, Iwasa Y, Tanaka T, Onodera H, Hiai H et al (1999) Persistent oxidative stress in human colorectal carcinoma, but not in adenoma. Free Radic Biol Med 27:401–410

    Article  PubMed  CAS  Google Scholar 

  15. Mizukami Y, Kono K, Kawaguchi Y, Akaike H, Kamimura K, Sugai H et al (2008) Localisation pattern of Foxp3+ regulatory T cells is associated with clinical behaviour in gastric cancer. Br J Cancer 98:148–153

    Article  PubMed  CAS  Google Scholar 

  16. Takahashi A, Kono K, Ichihara F, Sugai H, Amemiya H, Iizuka H et al (2003) Macrophages in tumor-draining lymph node with different characteristics induce T-cell apoptosis in patients with advanced stage-gastric cancer. Int J Cancer 104:393–399

    Article  PubMed  CAS  Google Scholar 

  17. Izawa S, Kono K, Mimura K, Kawaguchi Y, Watanabe M, Maruyama T et al (2011) H2O2 production within tumor microenvironment inversely correlated with infiltration of CD56(dim) NK cells in gastric and esophageal cancer: possible mechanisms of NK cell dysfunction. Cancer Immunol Immunother 60:1801–1810

    Article  PubMed  CAS  Google Scholar 

  18. Suzuki H, Onishi H, Wada J, Yamasaki A, Tanaka H, Nakano K et al (2010) VEGFR2 is selectively expressed by FOXP3high CD4+ Treg. Eur J Immunol 40:197–203

    Article  PubMed  CAS  Google Scholar 

  19. Schmielau J, Finn OJ (2001) Activated granulocytes and granulocyte-derived hydrogen peroxide are the underlying mechanism of suppression of t-cell function in advanced cancer patients. Cancer Res 61:4756–4760

    PubMed  CAS  Google Scholar 

  20. Malmberg KJ, Arulampalam V, Ichihara F, Petersson M, Seki K, Andersson T et al (2001) Inhibition of activated/memory (CD45RO(+)) T cells by oxidative stress associated with block of NF-kappaB activation. J Immunol 167:2595–2601

    PubMed  CAS  Google Scholar 

  21. Klemke CD, Brenner D, Weiss EM, Schmidt M, Leverkus M, Gulow K et al (2009) Lack of T-cell receptor-induced signaling is crucial for CD95 ligand up-regulation and protects cutaneous T-cell lymphoma cells from activation-induced cell death. Cancer Res 69:4175–4183

    Article  PubMed  CAS  Google Scholar 

  22. Lu B, Finn OJ (2008) T-cell death and cancer immune tolerance. Cell Death Differ 15:70–79

    Article  PubMed  Google Scholar 

  23. Takahashi A, Hanson MG, Norell HR, Havelka AM, Kono K, Malmberg KJ et al (2005) Preferential cell death of CD8+ effector memory (CCR7−CD45RA−) T cells by hydrogen peroxide-induced oxidative stress. J Immunol 174:6080–6087

    PubMed  CAS  Google Scholar 

  24. Mougiakakos D, Johansson CC, Jitschin R, Bottcher M, Kiessling R (2011) Increased thioredoxin-1 production in human naturally occurring regulatory T cells confers enhanced tolerance to oxidative stress. Blood 117:857–861

    Article  PubMed  CAS  Google Scholar 

  25. Cosentino M, Fietta AM, Ferrari M, Rasini E, Bombelli R, Carcano E et al (2007) Human CD4+CD25+ regulatory T cells selectively express tyrosine hydroxylase and contain endogenous catecholamines subserving an autocrine/paracrine inhibitory functional loop. Blood 109:632–642

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by a grant from the Ministry of Education, Culture, Sports, Science, and Technology of Japan.

Conflict of interest

There is no conflict of interest in the present study.

Author information

Authors and Affiliations

  1. First Department of Surgery, University of Yamanashi, Kofu and Tamaho, Japan

    Shinichirou Izawa, Kousaku Mimura, Mitsuaki Watanabe, Takanori Maruyama, Yoshihiko Kawaguchi, Hideki Fujii & Koji Kono

  2. Department of Surgery, National University of Singapore, Level 8, NUHS Tower Block, NUHS, 1E Kent Ridge Road, Singapore, 119228, Singapore

    Kousaku Mimura & Koji Kono

  3. Cancer Science Institute of Singapore, Singapore, Singapore

    Koji Kono

Authors
  1. Shinichirou Izawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kousaku Mimura
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mitsuaki Watanabe
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Takanori Maruyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yoshihiko Kawaguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hideki Fujii
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Koji Kono
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Koji Kono.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Izawa, S., Mimura, K., Watanabe, M. et al. Increased prevalence of tumor-infiltrating regulatory T cells is closely related to their lower sensitivity to H2O2-induced apoptosis in gastric and esophageal cancer. Cancer Immunol Immunother 62, 161–170 (2013). https://doi.org/10.1007/s00262-012-1327-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-012-1327-0

Keywords

Search

Navigation