Molecular, metabolic and functional CD4 T cell paralysis impedes tumor control

Abstract

ABSTRACTCD4 T cells are important effectors of anti-tumor immunity, yet the regulation of CD4 tumor-specific T (TTS) cells during cancer development is still unclear. We demonstrate that CD4 TTScells are initially primed in the tumor draining lymph node and begin to divide following tumor initiation. Distinct from CD8 TTScells and previously defined exhaustion programs, CD4 TTScell proliferation is rapidly frozen in place and differentiation stunted by a functional interplay of T regulatory cells and both intrinsic and extrinsic CTLA4 signaling. Together these mechanisms paralyze CD4 TTScell differentiation, redirecting metabolic and cytokine production circuits, and reducing CD4 TTScell accumulation in the tumor. Paralysis is actively maintained throughout cancer progression and CD4 TTScells rapidly resume proliferation and functional differentiation when both suppressive reactions are alleviated. Strikingly, Treg depletion alone reciprocally induced CD4 TTScells to themselves become tumor-specific Tregs, whereas CTLA4 blockade alone failed to promote T helper differentiation. Overcoming their paralysis established long-term tumor control, demonstrating a novel immune evasion mechanism that specifically cripples CD4 TTScells to favor tumor progression.