Cancer-associated fibroblasts affect intratumoral CD8þ and Foxp3þ T cells via IL6 in the tumor microenvironment

Takuya Kato, Kazuhiro Noma, Toshiaki Ohara, Hajime Kashima, Yuki Katsura, Hiroaki Sato, Satoshi Komoto, Ryoichi Katsube, Takayuki Ninomiya, Hiroshi Tazawa, Yasuhiro Shirakawa, Toshiyoshi Fujiwara

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Purpose: Cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME) play a central role in tumor progression. We investigated whether CAFs can regulate tumor-infiltrating lymphocytes (TILs) and their role in tumor immunosuppression. Experimental Design: A total of 140 cases of esophageal cancer were analyzed for CAFs and CD8þ or forkhead box protein 3 (FoxP3þ) TILs by IHC. We analyzed cytokines using murine or human fibroblasts and cancer cells. Murine-derived fibroblasts and cancer cells were also inoculated into BALB/c or BALB/c-nu/nu mice and the tumors treated with recombinant IL6 or anti-IL6 antibody. Results: CD8þ TILs and CAFs were negatively correlated in intratumoral tissues (P < 0.001), whereas FoxP3þ TILs were positively correlated (P < 0.001) in esophageal cancers. Cocul-tured Colon26 cancer cells and fibroblasts resulted in accelerated tumor growth in BALB/c mice, along with decreased CD8þ and increased FoxP3þ TILs, compared with cancer cells alone. In vitro, IL6 was highly secreted in both murine and human cancer cell/fibroblast cocultures. IL6 significantly increased Colon26 tumor growth in immune-competent BALB/c (P < 0.001) with fewer CD8þ TILs than untreated tumors (P < 0.001), whereas no difference in BALB/c-nu/nu mice. In contrast, FoxP3þ TILs increased in IL6-treated tumors (P < 0.001). IL6 antibody blockade of tumors cocultured with fibroblasts resulted not only in regression of tumor growth but also in the accumulation of CD8þ TILs in intratumoral tissues. Conclusions: CAFs regulate immunosuppressive TIL populations in the TME via IL6. IL6 blockade, or targeting CAFs, may improve preexisting tumor immunity and enhance the efficacy of conventional immunotherapies.

Original languageEnglish
Pages (from-to)4820-4833
Number of pages14
JournalClinical Cancer Research
Volume24
Issue number19
DOIs
Publication statusPublished - Oct 1 2018

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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