Induction of anergic or regulatory tumor-specific CD4+ T cells in the tumor-draining lymph node

• DOI: 10.1038/s41467-018-04524-x
• Publication Date: 2018-05-23T11:33:10Z
• Authors: Ruby Alonso; Héloïse Flament; Sébastien Lemoine; Christine Sedlik; Emanuel Bottasso; Isabel Péguillet; Virginie Prémel; Jordan Denizeau; Marion Salou; Aurélie Darbois; Nicolás Gonzalo N...; Benoit Salomon; David Gross; Eliane Piaggio; Olivier Lantz
• Keywords: 0301 basic medicine; Science; 610; [SDV.CAN]Life Sciences [q-bio]/Cancer; Adenocarcinoma of Lung; Lymphocyte Activation; T-Lymphocytes, Regulatory; Article; Cell Line; Mice; 03 medical and health sciences; Antigens, Neoplasm; Immune Tolerance; Animals; Humans; Clonal Anergy; Mice, Knockout; Q; Cell Differentiation; 3. Good health; Disease Models, Animal; HEK293 Cells; [SDV.IMM]Life Sciences [q-bio]/Immunology; Female; Tumor Escape; Lymph Nodes

AbstractCD4+T cell antitumor responses have mostly been studied in transplanted tumors expressing secreted model antigens (Ags), while most mutated proteins in human cancers are not secreted. The fate of Ag-specific CD4+T cells recognizing a cytoplasmic Ag in mice bearing autochthonous tumors is still unclear. Here we show, using a genetically engineered lung adenocarcinoma mouse model, that naive tumor-specific CD4+T cells are activated and proliferate in the tumor-draining lymph node (TdLN) but do not differentiate into effectors or accumulate in tumors. Instead, these CD4+T cells are driven toward anergy or peripherally-induced Treg (pTreg) differentiation, from the early stage of tumor development. This bias toward immune suppression is restricted to the TdLN, and is maintained by Tregs enriched in the tumor Ag-specific cell population. Thus, tumors may enforce a dominant inhibition of the anti-tumor CD4 response in the TdLN by recapitulating peripheral self-tolerance mechanisms.