Skip to main content

Advertisement

SpringerLink
Log in

The impact of ICOS+ regulatory T cells and Helicobacter pylori infection on the prognosis of patients with gastric and colorectal cancer: potential prognostic benefit of pre-operative eradication therapy

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

Abstract

It remains unclear whether Helicobacter pylori (H. pylori), a major cause of gastric cancer (GC), is involved in other intestinal cancers. In our previous study, ICOS+ Foxp3+ CD4+ T cells (ICOS+ Tregs) in GC tumors were identified as effector Tregs and associated with H. pylori. In the present study, the impact of ICOS+ Tregs on not only GC, but also colorectal cancer (CRC) and their prognosis was investigated in association with H. pylori. Tissue-infiltrating lymphocytes (TILs) purified from fresh tumor and sera were obtained from GC and CRC patients prospectively. % ICOS+ Tregs were analyzed by flow cytometry and their production of anti-H. pylori antibody (Hp-Ab) in sera was detected by ELISA. % ICOS+ Tregs were higher in GC and CRC patients with Hp-Ab than in those without Hp-Ab, including eradicated patients. ICOS+ Tregs purified had higher potential to produce IL-10 than ICOS− Tregs. For prognostic analysis, immunohistochemical analysis and ELISA were performed using archival fixed specimens and frozen sera, respectively, obtained from GC and CRC patients. Overall survival was longer in patients with low % ICOS+ Tregs than in those with high % ICOS+ Tregs, and patients with Hp-Ab showed shorter recurrence-free survival than those without Hp-Ab. These results suggested that ICOS+ Tregs in GC and CRC patients were closely associated with H. pylori in gastric epithelium and their prognosis, and that pre-operative H. pylori eradication has potential as a novel immunotherapy for GC and CRC patients.

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

Similar content being viewed by others

Abbreviations

CI:

Confidence interval

CRC:

Colorectal cancer

CT:

Cancer/testis

eTregs:

Effector Tregs

EC:

Esophageal cancer

GC:

Gastric cancer

HR:

Hazard ratio

H. pylori, Hp :

Helicobacter pylori

Hp-Ab:

H. pylori Antibody

IHC:

Immunohistochemistry

OC:

Ovarian cancer

OS:

Overall survival

PBMCs:

Peripheral blood mononuclear cells

pDC:

Plasmacytoid dendritic cell

RCC:

Renal cell carcinoma

RFS:

Recurrence-free survival

TILs:

Tumor tissue-infiltrating lymphocytes

TLRs:

Toll-like receptors

Tregs:

Regulatory T cell

References

  1. Alfarouk KO, Bashir AHH, Aljarbou AN et al (2019) The possible role of helicobacter pylori in gastric cancer and its management. Front Oncol 9:75. https://doi.org/10.3389/fonc.2019.00075

    Article  PubMed  PubMed Central  Google Scholar 

  2. Zumkeller N, Brenner H, Zwahlen M, Rothenbacher D (2006) Helicobacter pylori infection and colorectal cancer risk: a meta-analysis. Helicobacter 11:75–80. https://doi.org/10.1111/j.1523-5378.2006.00381.x

    Article  PubMed  Google Scholar 

  3. Butt J, Varga MG, Blot WJ et al (2019) Serologic response to helicobacter pylori proteins associated with risk of colorectal cancer among diverse populations in the United States. Gastroenterology 156(175–86):e2. https://doi.org/10.1053/j.gastro.2018.09.054

    Article  Google Scholar 

  4. Karkhah A, Ebrahimpour S, Rostamtabar M, Koppolu V, Darvish S, Vasigala VKR, Validi M, Nouri HR (2019) Helicobacter pylori evasion strategies of the host innate and adaptive immune responses to survive and develop gastrointestinal diseases. Microbiol Res 218:49–57. https://doi.org/10.1016/j.micres.2018.09.011

    Article  CAS  PubMed  Google Scholar 

  5. Chaturvedi R, de Sablet T, Coburn LA, Gobert AP, Wilson KT (2012) Arginine and polyamines in Helicobacter pylori-induced immune dysregulation and gastric carcinogenesis. Amino Acids 42:627–640. https://doi.org/10.1007/s00726-011-1038-4

    Article  CAS  PubMed  Google Scholar 

  6. Wing JB, Tanaka A, Sakaguchi S (2019) Human FOXP3(+) regulatory T cell heterogeneity and function in autoimmunity and cancer. Immunity 50:302–316. https://doi.org/10.1016/j.immuni.2019.01.020

    Article  CAS  PubMed  Google Scholar 

  7. Nishikawa H, Sakaguchi S (2014) Regulatory T cells in cancer immunotherapy. Curr Opin Immunol 27:1–7. https://doi.org/10.1016/j.coi.2013.12.005

    Article  CAS  PubMed  Google Scholar 

  8. Sugiyama D, Nishikawa H, Maeda Y et al (2013) Anti-CCR4 mAb selectively depletes effector-type FoxP3+CD4+ regulatory T cells, evoking antitumor immune responses in humans. Proc Natl Acad Sci U S A 110:17945–17950. https://doi.org/10.1073/pnas.1316796110

    Article  PubMed  PubMed Central  Google Scholar 

  9. Miyara M, Yoshioka Y, Kitoh A et al (2009) Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor. Immunity 30:899–911. https://doi.org/10.1016/j.immuni.2009.03.019

    Article  CAS  Google Scholar 

  10. deLeeuw RJ, Kost SE, Kakal JA, Nelson BH (2012) The prognostic value of FoxP3+ tumor-infiltrating lymphocytes in cancer: a critical review of the literature. Clin Cancer Res 18:3022–3029. https://doi.org/10.1158/1078-0432.CCR-11-3216

    Article  CAS  PubMed  Google Scholar 

  11. Haas M, Dimmler A, Hohenberger W, Grabenbauer GG, Niedobitek G, Distel LV (2009) Stromal regulatory T-cells are associated with a favourable prognosis in gastric cancer of the cardia. BMC Gastroenterol 9:65. https://doi.org/10.1186/1471-230X-9-65

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Shen Z, Zhou S, Wang Y, Li RL, Zhong C, Liang C, Sun Y (2010) Higher intratumoral infiltrated Foxp3+ Treg numbers and Foxp3+/CD8+ ratio are associated with adverse prognosis in resectable gastric cancer. J Cancer Res Clin Oncol 136:1585–1595. https://doi.org/10.1007/s00432-010-0816-9

    Article  CAS  PubMed  Google Scholar 

  13. Saito T, Nishikawa H, Wada H et al (2016) Two FOXP3(+)CD4(+) T cell subpopulations distinctly control the prognosis of colorectal cancers. Nat Med 22:679–684. https://doi.org/10.1038/nm.4086

    Article  CAS  PubMed  Google Scholar 

  14. Nagase H, Takeoka T, Urakawa S et al (2017) ICOS(+) Foxp3(+) TILs in gastric cancer are prognostic markers and effector regulatory T cells associated with Helicobacter pylori. Int J Cancer 140:686–695. https://doi.org/10.1002/ijc.30475

    Article  CAS  PubMed  Google Scholar 

  15. Ito T, Hanabuchi S, Wang YH, Park WR, Arima K, Bover L, Qin FX, Gilliet M, Liu YJ (2008) Two functional subsets of FOXP3+ regulatory T cells in human thymus and periphery. Immunity 28:870–880. https://doi.org/10.1016/j.immuni.2008.03.018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Landuyt AE, Klocke BJ, Colvin TB, Schoeb TR, Maynard CL (2019) Cutting edge: ICOS-deficient regulatory T cells display normal induction of Il10 but readily downregulate expression of Foxp3. J Immunol 202:1039–1044. https://doi.org/10.4049/jimmunol.1801266

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Collin M, McGovern N, Haniffa M (2013) Human dendritic cell subsets. Immunology 140:22–30. https://doi.org/10.1111/imm.12117

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Venerito M, Vasapolli R, Rokkas T, Delchier JC, Malfertheiner P (2017) Helicobacter pylori, gastric cancer and other gastrointestinal malignancies. Helicobacter 22(Suppl):1. https://doi.org/10.1111/hel.12413

    Article  Google Scholar 

  19. Kato R, Yamasaki M, Urakawa S et al (2018) Increased Tim-3(+) T cells in PBMCs during nivolumab therapy correlate with responses and prognosis of advanced esophageal squamous cell carcinoma patients. Cancer Immunol Immunother 67:1673–1683. https://doi.org/10.1007/s00262-018-2225-x

    Article  CAS  PubMed  Google Scholar 

  20. Kato M, Ota H, Okuda M et al (2019) Guidelines for the management of Helicobacter pylori infection in Japan: 2016 Revised Edition. Helicobacter. https://doi.org/10.1111/hel.12597

  21. Tang YL, Gan RL, Dong BH, Jiang RC, Tang RJ (2005) Detection and location of Helicobacter pylori in human gastric carcinomas. World J Gastroenterol 11:1387–1391. https://doi.org/10.3748/wjg.v11.i9.1387

    Article  PubMed  PubMed Central  Google Scholar 

  22. Fukase K, Kato M, Kikuchi S et al (2008) Effect of eradication of Helicobacter pylori on incidence of metachronous gastric carcinoma after endoscopic resection of early gastric cancer: an open-label, randomised controlled trial. The Lancet 372:392–397. https://doi.org/10.1016/s0140-6736(08)61159-9

    Article  Google Scholar 

  23. Ohira M, Toyokawa T, Sakurai K, Kubo N, Tanaka H, Muguruma K, Yashiro M, Onoda N, Hirakawa K (2016) Current status in remnant gastric cancer after distal gastrectomy. World J Gastroenterol 22:2424–2433. https://doi.org/10.3748/wjg.v22.i8.2424

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Liu J, Blake SJ, Yong MC et al (2016) Improved efficacy of neoadjuvant compared to adjuvant immunotherapy to eradicate metastatic disease. Cancer Discov 6:1382–1399. https://doi.org/10.1158/2159-8290.CD-16-0577

    Article  CAS  PubMed  Google Scholar 

  25. Blank CU, Rozeman EA, Fanchi LF et al (2018) Neoadjuvant versus adjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma. Nat Med 24:1655–1661. https://doi.org/10.1038/s41591-018-0198-0

    Article  CAS  Google Scholar 

  26. Kurose K, Ohue Y, Wada H et al (2015) Phase Ia Study of FoxP3+ CD4 Treg depletion by infusion of a humanized Anti-CCR4 antibody, KW-0761, in cancer patients. Clin Cancer Res 21:4327–4336. https://doi.org/10.1158/1078-0432.CCR-15-0357

    Article  CAS  PubMed  Google Scholar 

  27. McClain MS, Beckett AC, Cover TL (2017) Helicobacter pylori vacuolating toxin and gastric cancer. Toxins (Basel). https://doi.org/10.3390/toxins9100316

    Article  Google Scholar 

  28. Sheh A, Fox JG (2013) The role of the gastrointestinal microbiome in Helicobacter pylori pathogenesis. Gut Microbes 4:505–531. https://doi.org/10.4161/gmic.26205

    Article  PubMed  PubMed Central  Google Scholar 

  29. Wong SH, Zhao L, Zhang X et al (2017) Gavage of fecal samples from patients with colorectal cancer promotes intestinal carcinogenesis in germ-free and conventional mice. Gastroenterology 153(1621–33):e6. https://doi.org/10.1053/j.gastro.2017.08.022

    Article  Google Scholar 

  30. Thorburn CM, Friedman GD, Dickinson CJ, Vogelman JH, Orentreich N, Parsonnet J (1998) Gastrin and colorectal cancer: a prospective study. Gastroenterology 115:275–280. https://doi.org/10.1016/s0016-5085(98)70193-3

    Article  CAS  PubMed  Google Scholar 

  31. Cai Q, Gao YT, Chow WH et al (2006) Prospective study of urinary prostaglandin E2 metabolite and colorectal cancer risk. J Clin Oncol 24:5010–5016. https://doi.org/10.1200/JCO.2006.06.4931

    Article  CAS  PubMed  Google Scholar 

  32. Hoadley KA, Yau C, Hinoue T et al (2018) Cell-of-origin patterns dominate the molecular classification of 10,000 tumors from 33 types of cancer. Cell 173(291–304):e6. https://doi.org/10.1016/j.cell.2018.03.022

    Article  CAS  Google Scholar 

  33. Kersten K, Salvagno C, de Visser KE (2015) Exploiting the immunomodulatory properties of chemotherapeutic drugs to improve the success of cancer immunotherapy. Front Immunol 6:516. https://doi.org/10.3389/fimmu.2015.00516

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Terme M, Pernot S, Marcheteau E et al (2013) VEGFA-VEGFR pathway blockade inhibits tumor-induced regulatory T-cell proliferation in colorectal cancer. Cancer Res 73:539–549. https://doi.org/10.1158/0008-5472.CAN-12-2325

    Article  CAS  PubMed  Google Scholar 

  35. Yamamoto Y, Fujisaki J, Omae M, Hirasawa T, Igarashi M (2015) Helicobacter pylori-negative gastric cancer: characteristics and endoscopic findings. Dig Endosc 27:551–561. https://doi.org/10.1111/den.12471

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We thank all the patients who contributed to this study. We thank Kayoko Maekawa and Junko Yamagishi for their help.

Funding

This study was supported by Grants-in-Aid for Scientific Research (B) grant no. 19H03729.

Author information

Authors and Affiliations

  1. Department of Clinical Research in Tumor Immunology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita city, Osaka, 565-0871, Japan

    Shinya Urakawa, Kei Yamamoto, Kumiko Goto, Miya Haruna, Michinari Hirata, Akiko Morimoto-Okazawa, Kota Iwahori & Hisashi Wada

  2. Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, Japan

    Shinya Urakawa, Makoto Yamasaki, Tomoki Makino, Yukinori Kurokawa, Kei Yamamoto, Tsunekazu Mizushima & Yuichiro Doki

  3. Drug Discovery and Disease Research Laboratory, Shionogi and Co., Ltd, Toyonaka, Osaka, Japan

    Kumiko Goto, Miya Haruna & Michinari Hirata

  4. Department of Urology, Osaka University Graduate School of Medicine, Osaka, Japan

    Atsunari Kawashima

  5. Department of Pathology, Institute of Medical Science (Medical Research Center), Tokyo Medical University, Tokyo, Japan

    Eiichi Sato

  6. Department of Surgery and Science, Graduate School of Medical Sciences, Kyusyu University, Fukuoka, Japan

    Masaki Mori

Authors
  1. Shinya Urakawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Makoto Yamasaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tomoki Makino
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yukinori Kurokawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kei Yamamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kumiko Goto
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Miya Haruna
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Michinari Hirata
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Akiko Morimoto-Okazawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Atsunari Kawashima
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Kota Iwahori
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Tsunekazu Mizushima
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Eiichi Sato
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Masaki Mori
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Yuichiro Doki
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Hisashi Wada
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conception of the work: SU, MM, YD, and HW. Data collection and analysis: SU, TM, YK, KY, KG, MH, MH, TM, and ES. Manuscript writing/editing: AK, KI, and HW. Preparation of figures: MY and SU. Critical revision of the manuscript: AM-O, AK, KI, and HW. Final approval: all authors.

Corresponding author

Correspondence to Hisashi Wada.

Ethics declarations

Conflict of interest

The authors declare that they have no conflicts of interest.

Ethical approval and consent to participate

The present study was approved by the Institutional Ethics Committee of Osaka University Hospital (#13266–13, #8226–6) and performed in accordance with the Declaration of Helsinki. All samples were obtained with the patients’ informed consent.

Consent for publication

All the patients provided written general consent (#8226–6) to the use of their medical data and publication at the time of their first hospitalization.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

ICOS+ regulatory T cells in gastric and colorectal tumors were closely associated with H. pylori infection and the prognosis of these patients. Pre-operative H. pylori eradication has potential as a novel cancer immune therapy.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 397 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Urakawa, S., Yamasaki, M., Makino, T. et al. The impact of ICOS+ regulatory T cells and Helicobacter pylori infection on the prognosis of patients with gastric and colorectal cancer: potential prognostic benefit of pre-operative eradication therapy. Cancer Immunol Immunother 70, 443–452 (2021). https://doi.org/10.1007/s00262-020-02696-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-020-02696-4

Keywords

Search

Navigation