A key unknown of the functional space in tumor immunity is whether CD4 T cells depend on intratumoral MHCII cancer antigen recognition. MHCII-expressing, antigen-presenting cancer-associated fibroblasts (apCAFs) have been found in breast and pancreatic tumors and are considered to be immunosuppressive. This analysis shows that antigen-presenting fibroblasts are frequent in human lung non-small cell carcinomas, where they seem to actively promote rather than suppress MHCII immunity. Lung apCAFs directly activated the TCRs of effector CD4 T cells and at the same time produced C1q, which acted on T cell C1qbp to rescue them from apoptosis. Fibroblast-specific MHCII or C1q deletion impaired CD4 T cell immunity and accelerated tumor growth, while inducing C1qbp in adoptively transferred CD4 T cells expanded their numbers and reduced tumors. Collectively, we have characterized in the lungs a subset of antigen-presenting fibroblasts with tumor-suppressive properties and propose that cancer immunotherapies might be strongly dependent on in situ MHCII antigen presentation.

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.

A key unknown of the functional space in tumor immunity is whether physiologically relevant cancer antigen presentation occurs solely in draining lymph nodes versus tumors. Professional antigen presenting cells, i.e. the dendritic cells, are scarce and immature within tumors, greatly outnumbered by MHCII expressing non-hematopoietic cells, such as antigen-presenting cancer-associated fibroblasts (apCAFs). We hypothesized that after their exit from tumor-draining lymph nodes T cells depend on a second wave of antigen presentation provided in situ by structural cells. We show that dense apCAF regions in human lung tumors define hot immunological spots with increased numbers of CD4 T cells. The transcriptomic profile of human lung apCAFs aligned to that of pancreatic apCAFs across mice and humans and were both enriched for alveolar type II genes, suggesting an epithelial origin. Mechanistically, human apCAFs directly activated the TCRs of adjacent effector CD4 T cells and at the same time produced high levels of c1q, which acted on surface c1qbp on T cells to rescue them from apoptosis. Fibroblast-specific deletion of MHCII in mice impaired local MHCII immunity and accelerated tumor growth, while inducing c1qbp overexpression in adoptively transferred T cells expanded their numbers within tumors and reduced tumour burden. Collectively, our work shows that tumor T cell immunity post lymph node exit requires peripheral antigen presentation by a subset of CAFs and proposes a new conceptual framework upon which effective cancer immunotherapies can be built.

No abstract