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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 &lt; 0.001), whereas FoxP3 + TILs were positively correlated ( P &lt; 0.001) in esophageal cancers. Cocultured 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 , 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 &lt; 0.001) with fewer CD8 + TILs than untreated tumors ( P &lt; 0.001), whereas no difference in BALB/c- nu/nu mice. In contrast, FoxP3 + TILs increased in IL6-treated tumors ( P &lt; 0.001). IL6 antibody blockade of tumors cocultured with fibroblasts resulted not only in regression of tumor growth but also in the accumulation of CD8 + 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 .

Cancer-Associated Fibroblasts Affect Intratumoral CD8+ and FoxP3+ T Cells Via IL6 in the Tumor Microenvironment