Antigen presentation by tumor-associated macrophages mediates progenitor to terminal exhaustion transition in GBM and other solid tumors

Whereas terminally exhausted T (Tex_term) cells retain anti-tumor cytotoxic functions, the frequencies of stem-like progenitor exhausted T (Tex_prog) cells better reflect immunotherapeutic responsivity. Here, we examined the intratumoral cellular interactions that govern the transition to terminal T cell exhaustion. We defined a metric reflecting the intratumoral progenitor exhaustion-to-terminal exhaustion ratio (PETER), which decreased with tumor progression in solid cancers. Single cell analyses of Tex_prog cells and Tex_term cells in glioblastoma (GBM), a setting of severe T cell exhaustion, revealed disproportionate loss of Tex_prog cells over time. Exhaustion concentrated within tumor-specific T cell subsets, with cognate antigen exposure requisite for acquisition of the Tex_term phenotype. Tumor-associated macrophages (TAM) - not tumor cells - were the primary source of antigenic exposure governing the Tex_prog to Tex_term transition. TAM depletion increased frequencies of Tex_prog cells in multiple tumor models, increased PETER, and promoted responsiveness to PD-1 immunotherapy. Thus, targeting TAM - T cell interactions may further license checkpoint blockade responses.