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.