Tumor MHCII immunity requires in situ antigen presentation by cancer-associated fibroblasts

Abstract

Author contributions: Conception and design study, M.T.; Development of methodology, M.T.;Acquisition of data, D.K., K.G., E.A., P.S., A.P. and M.T.; Analysis and interpretation of data, D.K., K.M.V., C.T., and M.T.; Providing human samples, I. ABSTRACTIn situ antigen presentation is required to sustain active proliferating CD4 + T cells in tumours and to help form memory CD8 + T cells, but the antigen presenting cells (APCs) and pathways involved remain elusive.Cancer associated fibroblasts (CAFs) are prominent stromal constituent of solid tumors. Current immunological dogma considers that CAFs facilitate tumour immune escape. A new subset of MHCII antigen presenting cancer-associated fibroblasts (apCAFs) has been described, but their function remains unknown. Here we report a previously unrecognized function of apCAFs in sustaining CD4 + T cells in primary human and murine lung tumours. In response to IFNγ and oxidative stress in tumours CAFs upregulated MHCII. Fibroblast-specific targeted ablation of MHCII induced a hypometabolic hypoproliferative state in CD4 + T cells, which impacted MHCII and MHCI immunity, accelerating tumor growth. apCAFs directly presented MHCII-peptide (MCHIIp) complexes to activate the TCRs of CD4 + T cell. Highthrough-put profiling and blocking assays unveiled a novel CAF to T cell communication pathway via complement 1q binding on membrane C1qbp. Thus, apCAFs sustain anti-tumor CD4 + T cells via MHCIIp-TCR and C1q-C1qbp binding. Our studies pave the way to the design of novel immunotherapeutic strategies that will harness apCAFs to help sustain T cells inside solid tumours. Statement of significanceThis work challenges the immunological dogma that dominant physiological significance in tumour specific immunity comes only through professional APCs, leading to the design of novel MHCII fibroblastdirected strategies to sustain endogenous or adoptively transferred CD4 + T cells within solid tumors.

Cancer-associated fibroblasts in the single-cell era

“…scRNA-seq of samples from patients with ICC revealed a subpopulation expressing MHC class II-related genes such as CD74 , HLA-DRA and HLA-DRB1 54 . A recent study suggested that dense apCAF regions in human lung tumors define immunologically active regions with increased CD4 + T cell infiltration 91 . Leveraging published scRNA-seq data 37 and a defined metric for assessing physiologically relevant MHC class II gene expression, this study defined a population of potential apCAFs in human lung cancer and in mice, and proposed alveolar epithelial cells as their potential origin.…”

“…Since such treatment promotes accumulation of immune suppressive inflammatory CAFs, dual treatment with checkpoint inhibitors may provide important additive effects. c Enhancing the activity of antigen presenting CAFs and their ability to recruit CD4+ T cells 91 could promote anti-tumor immune activity. d Targeting inflammatory CAFs with IL1R antagonists (e.g.…”