Cancer-Associated Fibroblasts Affect Intratumoral CD8+and FoxP3+ T Cells via Interleukin 6 in the Tumor Microenvironment

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: 140 cases of esophageal cancer were analyzed for CAFs and CD8⁺or forkhead box protein 3 (FoxP3⁺) TILs by immunohistochemistry. 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/numice, and the tumors treated with recombinant interleukin 6 (IL-6) or anti-IL-6 antibody. Results: CD8⁺TILs and CAFs were negatively correlated in intra-tumoral tissues (P< 0.001), while FoxP3⁺TILs were positively correlated (P< 0.001) in esophageal cancers. Co-cultured Colon26 cancer cells and fibroblasts resulted in accelerated tumor growth in BALB/c mice, along with decreased CD8⁺and increased FoxP3⁺TILs, compared with cancer cells alone. In vitro, IL-6 was highly secreted in both murine and human cancer cell/fibroblast co-cultures. IL-6 significantly increased Colon26 tumor growth in immune-competent BALB/c (P< 0.001) with fewer CD8⁺TILs than untreated tumors (P< 0.001), whereas no difference in BALB/c-nu/numice. In contrast, FoxP3⁺TILs increased in IL-6-treated tumors (P< 0.001). IL-6 antibody blockade of tumors co-cultured with fibroblasts resulted not only in regression of tumor growth but also in the accumulation of CD8⁺TILs in intra-tumoral tissues. Conclusions:CAFs regulate immunosuppressive TIL populations in the TME via IL-6. IL-6 blockade, or targeting CAFs, may improve pre-existing tumor immunity and enhance the efficacy of conventional immunotherapies.

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