PRJNA874541
An Immunological Synapse Formation Between T Regulatory Cells and Cancer Associated Fibroblasts (CAFs) Promotes Tumor Development
Cancer associated fibroblasts (CAFs) have emerged as a dominant non-hematopoietic cell population in the tumor microenvironment (TME), serving diverse functions in tumor progression, invasion, matrix remodeling and resistance to therapy. Extensive molecular characterization revealed an increased heterogeneity in the CAF compartment and proposed an interaction between CAFs and tumor-infiltrating immune cells, which may shapes the tumor immune evasion. However, the precise mechanisms via which CAFs imprint on anti-tumor immunity remain poorly understood. Herein, we describe a synapse formation between aSMA+ CAFs and regulatory T cells (Tregs) in the TME. Specifically, Foxp3+ Tregs located in close proximity to aSMA+ CAFs in diverse types of tumor models as well as in biopsies from patients with melanoma and colorectal cancer. Notably, aSMA+ CAFs demonstrated the ability to phagocytose and process tumor antigens and exhibited a tolerogenic phenotype which instructed a Treg cell movement arrest together with Treg cell activation and proliferation, in an antigen-specific manner. Of interest aSMA+ CAFs showed an enrichment in double-membrane structures, resembling autophagosomes, in their cytoplasm. In a mechanistic view, conditional knockout of the autophagy pathway in aSMA+ CAFs promoted an inflammatory re-programming of CAFs, reduced Treg cell infiltration, attenuated tumor development, and potentiated the efficacy of immune checkpoint inhibitor immunotherapy. Overall, our findings reveal an immunosuppressive mechanism operating in the TME which entails formation of synapse between aSMA+ CAFs and Tregs in an autophagy-dependent fashion and raise the potential for development of CAF-targeted therapies in cancer.