| Autor: |
Toshiyoshi Fujiwara, Yasuhiro Shirakawa, Hiroshi Tazawa, Takayuki Ninomiya, Ryoichi Katsube, Satoshi Komoto, Hiroaki Sato, Yuki Katsura, Hajime Kashima, Toshiaki Ohara, Kazuhiro Noma, Takuya Kato |
| Rok vydání: |
2023 |
| DOI: |
10.1158/1078-0432.c.6527288 |
| Popis: |
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 < 0.001), whereas FoxP3+ TILs were positively correlated (P < 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 < 0.001) with fewer CD8+ TILs than untreated tumors (P < 0.001), whereas no difference in BALB/c-nu/nu mice. In contrast, FoxP3+ 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 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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
|
