Abstract

CD4+ T cells that express the forkhead box P3 (FOXP3) transcription factor function as regulatory T (Treg) cells and hinder effective immune responses against cancer cells1,2,3. Abundant Treg cell infiltration into tumors is associated with poor clinical outcomes in various types of cancers3,4,5,6,7. However, the role of Treg cells is controversial in colorectal cancers (CRCs), in which FOXP3+ T cell infiltration indicated better prognosis in some studies6,7,8,9. Here we show that CRCs, which are commonly infiltrated by suppression-competent FOXP3hi Treg cells, can be classified into two types by the degree of additional infiltration of FOXP3lo nonsuppressive T cells10. The latter, which are distinguished from FOXP3+ Treg cells by non-expression of the naive T cell marker CD45RA and instability of FOXP3, secreted inflammatory cytokines. Indeed, CRCs with abundant infiltration of FOXP3lo T cells showed significantly better prognosis than those with predominantly FOXP3hi Treg cell infiltration. Development of such inflammatory FOXP3lo non-Treg cells may depend on secretion of interleukin (IL)-12 and transforming growth factor (TGF)-β by tissues and their presence was correlated with tumor invasion by intestinal bacteria, especially Fusobacterium nucleatum. Thus, functionally distinct subpopulations of tumor-infiltrating FOXP3+ T cells contribute in opposing ways to determining CRC prognosis. Depletion of FOXP3hi Treg cells from tumor tissues, which would augment antitumor immunity, could thus be used as an effective treatment strategy for CRCs and other cancers, whereas strategies that locally increase the population of FOXP3lo non-Treg cells could be used to suppress or prevent tumor formation.

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Acknowledgements

We appreciate sample collection by members of the Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University. We thank J.B. Wing for helpful discussions and critical reading of this manuscript, and Y. Tada, K. Teshima, Y. Funabiki and Y. Nakamura for technical assistance. This study was supported by Grants-in-Aid for Scientific Research (A grant no. 26253030 (S.S.), B grant no. 26290054 (H. Nishikawa) and Challenging Exploratory Research grant no. 26670581 (H. Nishikawa)) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, the Core Research for Evolutional Science and Technology (CREST) program from the Japan Science and Technology Agency (S.S.), an H24–Clinical Cancer Research–general-006 grant from the Health and Labor Sciences Research Grants program (H. Nishikawa) from the Japan Ministry of Health, Labor and Welfare Grants-in-aid program for Research on Applying Health Technology and a Cancer Research Institute CLIP grant (H. Nishikawa). This study was done in part as a research program of the Project for Development of Innovative Research on Cancer Therapeutics (P-Direct), Ministry of Education, Culture, Sports, Science and Technology of Japan.

Author information

Author notes

    • Hiroyoshi Nishikawa

    Present address: Division of Cancer Immunology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Chiba, Japan.

Affiliations

  1. Experimental Immunology, World Premier International Research Center (WPI), Immunology Frontier Research Center, Graduate School of Medicine, Osaka University, Osaka, Japan.

    • Takuro Saito
    • , Hiroyoshi Nishikawa
    • , Daisuke Sugiyama
    • , Yuka Maeda
    • , Masahide Hamaguchi
    • , Naganari Ohkura
    •  & Shimon Sakaguchi
  2. Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan.

    • Takuro Saito
    • , Hisashi Wada
    • , Hirotsugu Nagase
    • , Junichi Nishimura
    • , Hirofumi Yamamoto
    • , Shuji Takiguchi
    • , Masaki Mori
    •  & Yuichiro Doki
  3. Department of Clinical Research in Tumor Immunology, Graduate School of Medicine, Osaka University, Osaka, Japan.

    • Hisashi Wada
  4. RIKEN Center for Integrative Medical Sciences (IMS), Kanagawa, Japan.

    • Yuji Nagano
    • , Koji Atarashi
    • , Takeshi Tanoue
    •  & Kenya Honda
  5. Department of Pathology, Institute of Medical Science (Medical Research Center), Tokyo Medical University, Tokyo, Japan.

    • Eiichi Sato
  6. Graduate School of Frontier Sciences, University of Tokyo, Chiba, Japan.

    • Wataru Suda
    •  & Masahira Hattori
  7. School of Veterinary Medicine, Azabu University, Kanagawa, Japan.

    • Hidetoshi Morita

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Contributions

H. Nishikawa and S.S. designed the research; T.S., H. Nishikawa, Y.N., D.S., K.A., Y.M., M. Hamaguchi, N.O., E.S., T.T. and W.S. performed experiments; T.S., H.W., H. Nagase, J.N., H.Y., S.T., M.M. and Y.D. collected samples and obtained clinical data; T.S., H. Nishikawa, H.W., W.S., H.M., M. Hattori, K.H., M.M., Y.D. and S.S. analyzed data; T.S., H. Nishikawa and S.S. wrote the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Hiroyoshi Nishikawa or Shimon Sakaguchi.

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DOI

https://doi.org/10.1038/nm.4086