Abstract 6537: Tumor IDO1 drives resistance to adoptive cell transfer by suppressing T cell recruitment and effector function

Abstract Adoptive cell transfer (ACT) has demonstrated potent anti-tumor efficacy in melanoma, yet therapeutic resistance frequently emerges within immunosuppressive tumor microenvironments. Indoleamine 2,3 dioxygenase 1 (IDO1) is a tryptophan catabolizing enzyme that generates kynurenine (Kyn), an immunomodulatory metabolite known to suppress effector T cell function. Here, we show that tumor overexpression of IDO1 undermines ACT efficacy through dual mechanisms of T cell exclusion and cytotoxic impairment. Using murine B16 melanoma cells engineered to overexpress IDO1 (B16IDO1), we observed elevated Kyn levels, reduced CXCL9/10 and CCL5 chemokine expression, and decreased intratumoral T cell infiltration. In vitro, IDO1 expressing tumor cells exhibited resistance to killing by activated CD8 PMEL T cells, a phenotype dependent on soluble factors in conditioned media and reversible with pharmacologic IDO1 inhibition. In vivo, adoptive transfer of either PMEL or TRP1 T cells, CD4 T cells specific for tyrosinase-related protein 1, failed to control B16IDO1 tumors, correlating with decreased infiltration, function, and survival. Pharmacologic blockade of IDO1 enhanced T cell infiltration and improved ACT mediated tumor control. Together, these findings identify IDO1 as a regulator of ACT resistance by suppressing T cell trafficking and effector activity. Complementary analyses of patient TIL, tumor, and serum samples are underway to assess correlations between IDO1/Kyn levels and immune cell burden, underscoring clinical relevance. Further studies extend this framework to human models, including IDO1+ melanoma xenografts and CAR T cells, to explore the translational potential of targeting the IDO1-Kyn-AHR axis to enhance cellular immunotherapy efficacy. Citation Format: Mamadou Alpha Bah, Rachana Maniyar, Jonathan F. Khan, Anais Assouvie, Sadna Budhu, Parwiz Abrahimi, Inna Serganova, Gabrielle A. Rizzuto, Taha Merghoub, Jedd D. Wolchok. Tumor IDO1 drives resistance to adoptive cell transfer by suppressing T cell recruitment and effector function abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6537.