Interaction between Kynurenine and the AhR is an effector mechanism of tumor immunosuppression and represents a potential immunotherapy target

Abstract

Abstract Although with notable impact on cancer treatment, immune-checkpoint blockade (ICB) have multiple mechanisms of resistance. The catabolism of Tryptophan into metabolites known as Kynurenines (Kyn) by enzymes such as IDO or TDO plays a major suppressive role in different tumor types. Recently it was shown that Kyn acts as an endogenous agonist of the Aryl-hydrocarbon Receptor (AhR). In order to gain a better understanding of this pathway, we sought to characterize the mechanisms of immunosuppression associated with AhR and evaluate its potential as therapeutic target. Gene-expression analysis of IDO-overexpressing melanomas (B16-IDO vs B16-WT) present reduced expression levels of Type-1 inflammatory genes, including IFNy, TNFa, Granzyme B and CD40. In addition, B16-IDO presents higher infiltration of TAMs, which up-regulate classic AhR-regulated genes (Cyp1a1 and Cyp1b1) and are differentially skewed towards an immunosuppressive M2-phenotype. Tumor-antigen specific CD8+T cells present reduced expression of activation markers (GzmB and CD44) and proliferation rate when primed by Kyn-treated BMDMs. Also, B16-IDO TAMs suppressed activation of CD8+T cells in vitro and their depletion abrogated tumor growth. Implantation of B16-IDOs in FoxP3-depleted mice prevents TAMs accumulation. Treatment of B16-IDO tumors with an AhR-specific antagonist (CH-223191) up-regulates MHC II in APCs, activation markers in CD8s and reduced frequency of T-regs. AhR inhibition slows down tumor growth and prolongs survival, which is improved in combination with PD-1 blockade. In summary, our findings demonstrate that targeting the Kyn pathway through AhR-inhibition represents a promising approach in cancer patients who are resistant to ICB.