Molecular, metabolic, and functional CD4 T cell paralysis in the lymph node impedes tumor control.

CD4 T cells are central effectors of anti-cancer immunity and immunotherapy, yet the regulation of CD4 tumor-specific T (T TS) cells is unclear. We demonstrate that CD4 T TS cells are quickly primed and begin to divide following tumor initiation. However, unlike CD8 T TS cells or exhaustion programming, CD4 T TS cell proliferation is rapidly frozen in place by a functional interplay of regulatory T cells and CTLA4. Together these mechanisms paralyze CD4 T TS cell differentiation, redirecting metabolic circuits, and reducing their accumulation in the tumor. The paralyzed state is actively maintained throughout cancer progression and CD4 T TS cells rapidly resume proliferation and functional differentiation when the suppressive constraints are alleviated. Overcoming their paralysis established long-term tumor control, demonstrating the importance of rapidly crippling CD4 T TS cells for tumor progression and their potential restoration as therapeutic targets. [Display omitted] • CD4 T TS cells are primed but rapidly "paralyzed" in the dLN during tumor development • Tregs and CTLA4 halt CD4 T TS cell activation, freezing proliferation, and differentiation • CD4 T TS cells retain latent functional capacity to resume tumor infiltration • Overcoming CD4 T TS cells paralysis enhances long-term tumor control How tumor-specific CD4 T cells differentiate and are regulated in response to tumors is not well understood. Guo et al. report that Tregs and CTLA4 rapidly program a dysfunctional CD4 T cell state in the lymph nodes that reduces tumor control. [ABSTRACT FROM AUTHOR]