IMMU-52. Novel Insights into T cell Exhaustion in GBM and other Solid Tumors

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Abstract While terminally exhausted T cells (Tex_term) retain important anti-tumor cytotoxic functions, it is the relative renewal of the stem-like progenitor exhaustion state (Tex_prog) that better reflects immunotherapeutic responsivity. The cellular interactions in a tumor microenvironment (TME) governing the transition between Tex_prog and Tex_term are not entirely established. We employed models of glioblastoma (GBM) and other solid tumors as paradigms of severe T cell exhaustion to better characterize the progression from Tex_prog to Tex_term within the TME. We observed a striking and disproportionate loss of Tex_prog within the tumor over time, leading to a low Progenitor Exhaustion to Terminal Exhaustion Ratio (PETER). However, we implicated tumor-associated macrophages (TAM), and not tumor cells, as the key source of antigenic exposure governing the Tex_prog to Tex_term transition. TAM depletion elicited increases to PETER across multiple tumor models, corresponding to enhanced anti-PD1 responses and tumor control. Moreover, T cell progression from Tex_prog to Tex_term is associated with T cell upregulation of the transcription factor TOX and expression of TIM3. We additionally reveal that T cell upregulation of tumor necrosis factor receptor type II (TNFR2) coincides with the Tex_prog to Tex_term transition. Knocking out TNFR2 affords a novel population of T cells that express TIM3 but possess diminished TOX levels and functional characteristics of both Tex_prog and Tex_term. TIM3+ TNFR2 KO T cells exhibit reduced exhaustion transcriptional programs and enhanced AP1 pathway signatures. Finally, TNFR2 KO mice demonstrate improved T cell-dependent control of both tumor and chronic lymphocytic choriomeningitis (cLCMV) infection, while pharmacologic antagonism of TNFR2 licenses responses to checkpoint blockade in multiple subcutaneous and intracranial tumor models. These findings identify the targeting of both TAM and T cell TNFR2 as viable means for influencing T cell differentiation states and licensing immunotherapeutic responses in GBM and other solid tumors.

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