Significant advances have been made in basic biology and manipulation of the immune system in the context of cancer. However, a major factor limiting the magnitude and durability of favorable outcomes from both traditional cancer therapies (e.g., chemotherapy, radiation) and novel immunotherapies (e.g., adoptive cell transfer, cancer vaccines) remains the persistent state of immunosuppression induced and sustained by cancers. Further understanding of mechanisms controlling immunosuppression in cancer is critical to the advancement of cancer therapeutics. In particular, appealing novel targets for reversing immunosuppression in cancer need to be identified. The ideal characteristic of such targets should be their potential to mediate multiple potential immunosuppressive mechanisms, improving the translatability of these interventions to multiple cancer types. The aryl hydrocarbon receptor (AhR) is a unique nexus for signals mediating immunosuppression. AhR promiscuously binds many ligands with aromatic, planar structures including exogenous (such as the pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin) and endogenous compounds (such as the tryptophan-derived catabolic product kynurenine (Kyn) and photoproduct 6-formylindolo[3,2-b]carbazole). The tryptophan catabolic pathway has emerged as a critical, multi-faceted regulator of immunosupression in cancer and other diseases, and many of these functions are mediated by Kyn, the soluble product of the tryptophan-degrading enzymes tryptophan- and indoleamine-2,3-dioxygenase (TDO and IDO, respectively). Many studies have correlated tumor progression and clinical outcomes with tryptophan catabolic levels or the activity of IDO and TDO. Targeting the AhR pathway as opposed to either IDO (whose inhibitors are currently in phase I clinical trials for cancer) or TDO may ultimately prove to be a more effective and widely applicable anti-immunosuppression strategy in cancer therapeutics that addresses the immunosuppressive effects of both enzymatic pathways. In this proposal, we utilize a biomaterials-based approach to inhibit the AhR pathway in the B16 melanoma system in mice. The goals of this work are: 1) to longitudinally evaluate the mechanisms of action of AhR in tumor establishment and tumor-associated immunosuppression using localized delivery of controlled release nano and microparticles containing an AhR antagonist and 2) test the efficacy of AhR antagonism as a paradigm for boosting host anti-tumor immunity in the context of chemotherapeutic and immunotherapeutic interventions. This study will have broad impact in the fields of cancer biology and therapy, immunology, and AhR biology.
A significant barrier to cancer therapeutics, particularly novel approaches such as cancer vaccines and immunotherapy, remains the persistent immunosuppressive microenvironment generated by tumors. In this proposal we present a biomaterials-based approach for local, sustained delivery of an inhibitor of the aryl hydrocarbon receptor, a unique ligand-activated transcription factor that has been shown to mediate multiple potential immunosuppressive mechanisms (particularly as a receptor the tryptophan catabolite kynurenine);this strategy integrates engineering principles in biomaterials and the targeting of an immunomodulatory pathway with a novel role in cancer immunology. The results of these studies will provide invaluable insight into the basic biology of the aryl hydrocarbon receptor in cancer pathogenesis, preclinical evaluation of the potential therapeutic efficacy of inhibitors of this receptor as novel immunomodulatory approach, and further characterize the effects of the aryl hydrocarbon receptor pathway on immunity.
