MHC-II+ fibroblasts (apCAFs), detected in abundance in TME of human NSCLC, triggered activation of autologous, freshly sorted CD4+ NSCLC TILs upon coculture. Activation was MHC-II-dependent. Human and mouse apCAFs were phenotypically similar, and a requirement for IFNγ and in vivo acquisition of tumor antigen was shown for apCAFs in mice. C1q overexpression was detected on human apCAFs, and its ligand, C1qbp, was detected by FACS on primary human TILs. Both human and mouse CD4+ T cells were rescued from apoptosis by C1q – implicating C1q as an extrinsic pro-survival signal.
Contributed by Margot O’Toole
ABSTRACT: 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 Info: (1) Institute of Bioinnovation, Biomedical Sciences Research Center "Alexander Fleming," Vari, Greece. (2) Institute of Bioinnovation, Biomedical Sciences Research Center "Alexande
Author Info: (1) Institute of Bioinnovation, Biomedical Sciences Research Center "Alexander Fleming," Vari, Greece. (2) Institute of Bioinnovation, Biomedical Sciences Research Center "Alexander Fleming," Vari, Greece. (3) Greek Research Infrastructure for Personalized Medicine, Medical School, National and Kapodistrian University of Athens, Athens, Greece. (4) Institute of Bioinnovation, Biomedical Sciences Research Center "Alexander Fleming," Vari, Greece. (5) Institute of Bioinnovation, Biomedical Sciences Research Center "Alexander Fleming," Vari, Greece. (6) Institute of Bioinnovation, Biomedical Sciences Research Center "Alexander Fleming," Vari, Greece. (7) Institute of Bioinnovation, Biomedical Sciences Research Center "Alexander Fleming," Vari, Greece. (8) Institute of Bioinnovation, Biomedical Sciences Research Center "Alexander Fleming," Vari, Greece. (9) Institute of Bioinnovation, Biomedical Sciences Research Center "Alexander Fleming," Vari, Greece. (10) Institute of Bioinnovation, Biomedical Sciences Research Center "Alexander Fleming," Vari, Greece. Greek Research Infrastructure for Personalized Medicine, Medical School, National and Kapodistrian University of Athens, Athens, Greece. (11) Animal House Facility, Biomedical Sciences Research Center "Alexander Fleming," Vari, Greece. (12) Department of Pathology, Sotiria Chest Hospital, Athens, Greece. (13) Department of Respiratory Medicine, Sotiria Chest Hospital, Athens, Greece. (14) Department of Thoracic Surgery, Sotiria Chest Hospital, Athens, Greece. (15) Department of Thoracic Surgery, Sotiria Chest Hospital, Athens, Greece. (16) Department of Pathology, Medical School, University of Crete, Crete, Greece. (17) Department of Thoracic Surgery, Sotiria Chest Hospital, Athens, Greece. (18) Institute of Bioinnovation, Biomedical Sciences Research Center "Alexander Fleming," Vari, Greece. Greek Research Infrastructure for Personalized Medicine, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
