GSE211738
Regulatory T cells and CTLA4-mediated proliferative and functional paralysis suppress anti-tumor CD4 T cell responses and impede tumor control
CD4 T cell help is critical for tumor control and the efficacy of immunotherapy. Yet, in contrast to CD8 T cells, CD4 tumor-specific T helper (Th) cell differentiation and function during cancer progression is unclear. We demonstrate that after priming, tumor-specific CD4 T cells in the draining lymph node (dLN) are rapidly frozen into a proliferatively paralyzed state, with concomitant immature Th-fate commitment, insufficient cellular metabolism and minimal tumor-infiltration. Overcoming these dysfunctions during tumor growth restarted T cell proliferation and differentiation to enable tumor control, identifying the requirement for tumor-induced CD4 T cell dysfunction to enable cancer progression. CD4 T cell dysfunction is regulated through an unlinked two-hit mechanism wherein natural (n)Treg modulation of antigen presentation and CTLA4 inhibited tumor-specific CD4 T cell-intrinsic signal integration diminish T cell activation to freeze the cells and prevent help. Targeting either nTreg or CTLA4 alone restored proliferation but failed to promote further effector T helper differentiation; only combination therapy fully restored anti-tumor CD4 T cells responses. Thus, our study demonstrates a complex regulatory system that restricts tumor-specific CD4 T cells in cancer and provides insight into therapeutic strategies for tumor control. Overall design: SMARTA cells from day 8 tumor inguinal lymph nodes of WT or Treg-depleted mice treated with anti-CTLA4 or isotype antibody. Freshly isolated naive SMARTA cells were used as naive control