Using a genetically engineered autochthonous lung adenocarcinoma mouse model expressing a cytoplasmic neoantigen, Alonso et al. demonstrate that naive, tumor antigen (Ag)-specific CD4+ T cells become partially activated and proliferate in the tumor-draining lymph node (TdLN), but do not accumulate in the tumor regardless of Ag load or tumor size. Instead, the majority of these cells become anergic, and a small but significant fraction independently differentiate into peripherally-induced pTregs. CD4+ T cell anergy required continuous Ag presentation by the tumor and was dependent on the host Tregs present in the TdLN.
CD4(+) 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.