Modulating AhR in tumor and lymphoid microenvironments via local drug delivery

描述（由申请人提供）：在癌症背景下，在基础生物学和免疫系统操作方面取得了重大进展。然而，限制传统癌症疗法（例如，化疗，放疗）和新的免疫疗法（例如，过继性细胞转移、癌症疫苗）仍然是由癌症诱导和维持的免疫抑制的持续状态。进一步了解癌症中控制免疫抑制的机制对癌症治疗的进展至关重要。特别是，需要确定用于逆转癌症中免疫抑制的有吸引力的新靶点。这些靶点的理想特征应该是它们有可能介导多种潜在的免疫抑制机制，提高这些干预措施对多种癌症类型的可转化性。芳香烃受体（AhR）是介导免疫抑制的信号的独特联系。AhR混杂地结合许多具有芳香族平面结构的配体，包括外源性化合物（如污染物2，3，7，8-四氯二苯并-对-二恶英）和内源性化合物（如Dahan衍生的分解代谢产物犬尿氨酸（Kyn）和光产物6-甲酰吲哚并[3，2-B]咔唑）。色氨酸分解代谢途径已经成为癌症和其他疾病中免疫抑制的关键的多方面调节剂，并且这些功能中的许多功能由Kyn介导，Kyn是色氨酸降解酶色氨酸-和吲哚胺-2，3-双加氧酶（分别为TDO和IDO）的可溶性产物。许多研究已经将肿瘤进展和临床结果与色氨酸分解代谢水平或IDO和TDO的活性相关联。靶向AhR途径，而不是IDO（其抑制剂目前处于癌症的I期临床试验中）或TDO 可能最终被证明是一种更有效和广泛适用的抗免疫抑制策略，在癌症治疗中，解决了两种酶途径的免疫抑制作用。在这个提议中，我们利用基于生物材料的方法来抑制小鼠B16黑色素瘤系统中的AhR通路。这项工作的目标是：1）使用含有AhR拮抗剂的控释纳米和微粒的局部递送纵向评估AhR在肿瘤建立和肿瘤相关免疫抑制中的作用机制，和2）测试AhR拮抗作用作为在化学治疗和免疫干预的背景下增强宿主抗肿瘤免疫的范例的功效。这项研究将在癌症生物学和治疗，免疫学和AhR生物学领域产生广泛的影响。

DESCRIPTION (provided by applicant): 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.