An Immunological Synapse Formation Between T Regulatory Cells and Cancer-Associated Fibroblasts Promotes Tumour Development: Secretomics

ABSTRACT: Cancer-associated fibroblasts (CAFs) have emerged as a dominant non-hematopoietic cell population in the tumour microenvironment (TME), serving diverse functions in tumour progression, invasion, matrix remodelling and resistance to therapy. Extensive molecular characterization revealed an increased heterogeneity in the CAF compartment and proposed an interaction between CAFs and tumour-infiltrating immune cells, which may shape tumour immune evasion. However, the precise mechanisms via which CAFs imprint on anti-tumour immunity remain poorly understood. Herein, we describe a synapse formation between α-SMA+ CAFs and regulatory T cells (Tregs) in the TME. Specifically, Foxp3+ Tregs were localized close to α-SMA+ CAFs in diverse types of tumour models as well as in biopsies from melanoma and colorectal cancer patients. Notably, α-SMA+ CAFs demonstrated the ability to phagocytose and process tumour antigens and exhibited a tolerogenic phenotype which instructed a Treg cell movement arrest with Treg cell activation and proliferation, in an antigen-specific manner. Of interest, α-SMA+ CAFs were characterized by the presence of double-membrane structures, resembling autophagosomes, in their cytoplasm, while analysis of single-cell transcriptomic data pointed autophagy and antigen processing/presentation pathways to be enriched in α-SMA-expressing CAF clusters. In a mechanistic view, conditional knockout of the autophagy pathway in α-SMA+ CAFs promoted an inflammatory re-programming of CAFs, reduced Treg cell infiltration, attenuated tumour development, and potentiated the efficacy of immune checkpoint inhibitor immunotherapy. Overall, our findings reveal an immunosuppressive mechanism operating in the TME, which entails the formation of synapses between α-SMA+ CAFs and Tregs in an autophagy-dependent fashion and raises the potential for the development of CAF-targeted therapies in cancer. Here we submit the secretome proteomic analyses.

INSTRUMENT(S): Q Exactive HF-X

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Skin, Fibroblast

DISEASE(S): Melanoma

SUBMITTER: Martina Samiotaki  

LAB HEAD: Panayotis Verginis

PROVIDER: PXD047038 | Pride | 2024-05-08

REPOSITORIES: Pride