Abstract
Background Cancer associated fibroblasts (CAF) are important component in tumor microenvironment and has been reported contributes to tumor progression through many mechanisms, however, the detailed mechanism underling immune-suppression effect are not clearly defined. Methods In this study, human breast cancer-derived cancer associated fibroblasts was cultured, and CAF-derived exosomes in culture medium was isolated. Cancer cell migration was evaluated by transwell and wound healing assay, miR-92 binding to the LATS2 3’ untranslated region was validated by luciferase report assay, and underlying mechanism was investigated by chromatin immunoprecipitation and Immunoprecipitation. Results After treatment by CAF-derived exosomes, breast cancer cells express higher PD-L1, accompanied with increased miR-92 expression. Increased PD-L1 expression which induced by CAF- derived exosomes significantly promotes apoptosis and impaired proliferation of T cell. proliferation and migration of breast cancer cells was increased after transfection of miR-92, LATS2 was recognized as target gene of miR-92, which was proved by luciferase assay. Immunoprecipitation (IP) shown that LATS2 can interact with YAP1, after nuclear translocation, YAP1 could binds to enhancer region of PD-L1 to promotes transcription activity, which was confirmed by chromatin immunoprecipitation (ChIP). Furthermore, animal study confirmed that cancer associated fibroblasts significantly promotes tumor progression and impaired function of tumor infiltrated immune cells in vivo. Conclusion Our data revealed a novel mechanism which can induce immune suppression in tumor microenvironment.
Nano-Strategies to Target Breast Cancer-Associated Fibroblasts: Rearranging the Tumor Microenvironment to Achieve Antitumor Efficacy
