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 (TTS) cells is unclear. We demonstrate that CD4 TTS cells are quickly primed and begin to divide following tumor initiation. However, unlike CD8 TTS cells or exhaustion programming, CD4 TTS cell proliferation is rapidly frozen in place by a functional interplay of regulatory T cells and CTLA4. Together these mechanisms paralyze CD4 TTS cell differentiation, redirecting metabolic circuits, and reducing their accumulation in the tumor. The paralyzed state is actively maintained throughout cancer progression and CD4 TTS 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 TTS cells for tumor progression and their potential restoration as therapeutic targets. [Display omitted] •CD4 TTS cells are primed but rapidly “paralyzed” in the dLN during tumor development•Tregs and CTLA4 halt CD4 TTS cell activation, freezing proliferation, and differentiation•CD4 TTS cells retain latent functional capacity to resume tumor infiltration•Overcoming CD4 TTS 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.