Guo et al. demonstrated that during early cancer development, suboptimal priming of tumor-specific CD4+ T cells (CD4 TTS) in the dLN induced a unique “paralyzed” state, impeding their proliferation and differentiation and reducing tumor infiltration. Coordination of Tregs and CTLA-4 reduced APC and CD4 TTS activation, abrogated Th fate commitment and transcriptional activation, reprogrammed metabolism toward oxidative phosphorylation, and reduced tumor control. CTLA-4 blockade alone restored CD4 TTS proliferation, and dual Treg depletion and CTLA-4 blockade enabled effector differentiation and metabolic reorganization leading to enhanced long-term tumor control.
Contributed by Shishir Pant
ABSTRACT: 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.