Cancer-Associated Fibroblasts Affect Intratumoral CD8+ and FoxP3+ T Cells Via IL6 in the Tumor Microenvironment
Published version of a preprint
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 CD8 + or forkhead box protein 3 (FoxP3 + ) 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: CD8 + TILs and CAFs were negatively correlated in intratumoral tissues ( P + TILs were positively correlated ( P + and increased FoxP3 + 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 + TILs than untreated tumors ( P nu/nu mice. In contrast, FoxP3 + TILs increased in IL6-treated tumors ( P + 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. Clin Cancer Res; 24(19); 4820-33. ©2018 AACR .
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CAFs reduce CD8+ T cell recruitment by releasing IL-6 and TGF-β, inhibiting their cytotoxic activity against tumor cells.
“They also reduce CD8+ T cell recruitment by releasing IL-6 and TGF-β, inhibiting their cytotoxic activity against tumor cells 75,76.”
From TBX3 shapes an immunosuppressive microenvironment and induces immunotherapy resistance (2025) · cites this paper as [75]
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- Authors
- Kato, T., Noma, K., Ohara, T., Kashima, H., Katsura, Y., Sato, H., Komoto, S., Katsube, R., Ninomiya, T., Tazawa, H., Shirakawa, Y., & Fujiwara, T.
- Affiliations
- Okayama University (JP)
- Corresponding author
- Noma, Kazuhiro
- ORCID
- Venue
- Clinical Cancer Research
- Published
- 2018-10-01
- Volume
- 24
- Issue
- 19
- Pages
- 4820-4833
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- OpenAlex
- W2809125618
- Cited by
- 367
- References
- 8
- Citations by year
- 2026: 26 · 2025: 46 · 2024: 47 · 2023: 66 · 2022: 54 · 2021: 64 · 2020: 35 · 2019: 20 · 2018: 9
- FWCI
- 12.10
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- The Ministry of Education, Science and Culture, Japan (16K10499)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- cancer-associated fibroblasts, tumor microenvironment, CD8+ T cells, Foxp3+ regulatory T cells, interleukin-6, esophageal cancer, tumor-infiltrating lymphocytes, tumor immunosuppression, tumor growth, immunotherapy
- MeSH terms
- Cancer-Associated Fibroblasts, Aged, Animals, Esophageal Neoplasms, Female, Humans, Male, Interleukin-6, Gene Expression Regulation, Neoplastic, Lymphocytes, Tumor-Infiltrating, Cell Line, Tumor, Mice, Forkhead Transcription Factors, Tumor Microenvironment, Heterografts
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