| Autor: |
Konstantinos Potaris, Kleio Verrou, Konstantinos Vachlas, Maria Tsoumakidou, Anastasios Koutsopoulos, Alejandro Prados, Petros Stamoulis, Emmanouil Aerakis, Katerina Goudevenou, Ioannis Vamvakaris, Evangelos Kaniaris, Christos Tzaferis, Evangelos Sepsas, Dimitra Kerdidani |
| Rok vydání: |
2020 |
| Předmět: |
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| Popis: |
In 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 up-regulated 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 significance This 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 fibroblast-directed strategies to sustain endogenous or adoptively transferred CD4+ T cells within solid tumors. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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