Varveri et al. investigated mechanisms used by CAFs to modulate antitumor immunity and contribute to cancer immunotherapy resistance. In multiple tumor models and patient biopsies, Foxp3+ Tregs preferentially accumulated in the TME in α-SMA+ CAF-rich areas, and formed synapses with α-SMA+ CAFs in an antigen-specific manner. Mechanistically, α-SMA+CAFs phagocytosed, processed, and presented tumor antigens via autophagy, which promoted Treg activation and proliferation. Ablation of CAF autophagy decreased Tregs and reprogrammed CAFs into a proinflammatory phenotype that potentiated the efficacy of dual ICB.
Contributed by Katherine Turner
ABSTRACT: Cancer-associated fibroblasts (CAFs) have emerged as a dominant non-hematopoietic cell population in the tumour microenvironment, serving diverse functions in tumour progression. However, the mechanisms via which CAFs influence the anti-tumour immunity remain poorly understood. Here, using multiple tumour models and biopsies from cancer patients, we report that _-SMA(+) CAFs can form immunological synapses with Foxp3(+) regulatory T cells (Tregs) in tumours. Notably, _-SMA(+) CAFs can phagocytose and process tumour antigens and exhibit a tolerogenic phenotype which instructs movement arrest, activation and proliferation in Tregs in an antigen-specific manner. Moreover, _-SMA(+) CAFs display double-membrane structures resembling autophagosomes in their cytoplasm. Single-cell transcriptomic data showed an enrichment in autophagy and antigen processing/presentation pathways in _-SMA-expressing CAF clusters. Conditional knockout of Atg5 in _-SMA(+) CAFs promoted inflammatory re-programming in CAFs, reduced Treg cell infiltration and attenuated tumour development. Overall, our findings reveal an immunosuppressive mechanism entailing the formation of synapses between _-SMA(+) CAFs and Tregs in an autophagy-dependent manner.
Author Info: (1) Center of Clinical, Experimental Surgery & Translational Research, Biomedical Research Foundation Academy of Athens, Athens, Greece. Laboratory of Immune Regulation and Toleran
Author Info: (1) Center of Clinical, Experimental Surgery & Translational Research, Biomedical Research Foundation Academy of Athens, Athens, Greece. Laboratory of Immune Regulation and Tolerance, Division of Basic Sciences, Medical School, University of Crete, Heraklion, Greece. (2) Center of Clinical, Experimental Surgery & Translational Research, Biomedical Research Foundation Academy of Athens, Athens, Greece. Laboratory of Immune Regulation and Tolerance, Division of Basic Sciences, Medical School, University of Crete, Heraklion, Greece. (3) Laboratory of Immune Regulation and Tolerance, Division of Basic Sciences, Medical School, University of Crete, Heraklion, Greece. Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology, Heraklion, Greece. (4) Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK. (5) Center of Clinical, Experimental Surgery & Translational Research, Biomedical Research Foundation Academy of Athens, Athens, Greece. (6) Center of Basic Research, Biomedical Research Foundation Academy of Athens, Athens, Greece. (7) 2nd Department of Pathology, National and Kapodistrian University of Athens, Attikon University Hospital, Athens, Greece. (8) JJP Biologics, Warsaw, Poland. (9) Electron Microscopy Laboratory, University of Crete, Heraklion, Greece. (10) Institute for Bioinnovation, Biomedical Sciences Research Centre Alexander Fleming, Vari, Athens, 166 72, Greece. (11) 2nd Department of Pathology, National and Kapodistrian University of Athens, Attikon University Hospital, Athens, Greece. (12) Laboratory of Biology, School of Medicine, Medical School National and Kapodistrian University of Athens, Athens, Greece. (13) Laboratory of Biology, School of Medicine, Medical School National and Kapodistrian University of Athens, Athens, Greece. Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine Carl Gustav Carus of TU Dresden, Dresden, Germany. (14) Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK. Laboratory of Biology, School of Medicine, Medical School National and Kapodistrian University of Athens, Athens, Greece. (15) Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK. (16) Center of Clinical, Experimental Surgery & Translational Research, Biomedical Research Foundation Academy of Athens, Athens, Greece. pverginis@uoc.gr. Laboratory of Immune Regulation and Tolerance, Division of Basic Sciences, Medical School, University of Crete, Heraklion, Greece. pverginis@uoc.gr. Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology, Heraklion, Greece. pverginis@uoc.gr. Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine Carl Gustav Carus of TU Dresden, Dresden, Germany. pverginis@uoc.gr.
