Modulating AhR in tumor and lymphoid microenvironments via local drug delivery

通过局部药物递送调节肿瘤和淋巴微环境中的 AhR

• 批准号: 8721709
• 负责人: Gregory Lee Szeto
• 金额: $ 5.51万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8721709
• 关键词: Address; Adoptive Cell Transfers; Adverse effects; Animals; Antigens; Aryl Hydrocarbon Receptor; Autocrine Communication; Autoimmunity; Binding; Biocompatible; Biocompatible Materials; Biological; Biology; Cancer Biology; Cancer Immunology Science; Cancer Vaccines; Carbazoles; Catabolism; Cell physiology; Characteristics; Clinical; Complex; Cyclophosphamide; Dendritic Cells; Development; Diet; Dioxygenases; Disease; Disease model; Dissection; Drug Delivery Systems; Engineering; Enzymes; Evaluation; Exhibits; Future; Gap Junctions; Goals; Growth; Homeostasis; Immune; Immune system; Immunity; Immunology; Immunosuppression; Immunosuppressive Agents; Immunotherapeutic agent; Immunotherapy; In Situ; Injection of therapeutic agent; Intervention; Kinetics; Knockout Mice; Kynurenine; Ligands; Light; Literature; Lymphoid; Malignant Neoplasms; Mediating; Methods; Modeling; Mus; Nature; Outcome; Pathogenesis; Pathway interactions; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Play; Primary Neoplasm; Process; Radiation; Reagent; Receptor Inhibition; Receptor Signaling; Regulatory T-Lymphocyte; Resolution; Role; Signal Transduction; Site; Solutions; Structure; System; T cell differentiation; T-Lymphocyte; Tetrachlorodibenzodioxin; Therapeutic; Time; Toxic effect; Transgenic Organisms; Treatment Efficacy; Tryptophan; Tumor Immunity; Ultrasonography; Vaccination; Work; activating transcription factor; base; cancer immunotherapy; cancer therapy; cancer type; carbazole; carcinogenesis; chemotherapy; controlled release; design; efficacy testing; genetic manipulation; immunogenicity; immunoregulation; improved; indoleamine; inhibitor/antagonist; insight; local drug delivery; lymph nodes; lymphoid neoplasm; macrophage; melanoma; minimally invasive; nano; novel; novel strategies; particle; pollutant; pre-clinical; preclinical evaluation; pressure; public health relevance; receptor; research study; subcutaneous; therapeutic target; tumor; tumor progression; tumorigenic

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.

描述（由申请人提供）：在癌症的基础生物学和免疫系统操作方面已经取得了重大进展。然而，限制传统癌症疗法（例如化疗、放疗）和新型免疫疗法（例如过继细胞移植、癌症疫苗）有利结果的程度和持久性的一个主要因素仍然是癌症诱导和维持的免疫抑制的持续状态。进一步了解控制癌症免疫抑制的机制对于癌症治疗的进步至关重要。特别是，需要确定逆转癌症免疫抑制的有吸引力的新靶标。此类靶点的理想特征应该是它们具有介导多种潜在免疫抑制机制的潜力，从而提高这些干预措施对多种癌症类型的可转化性。芳烃受体 (AhR) 是介导免疫抑制信号的独特纽带。 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（例如污染物 2,3,7,8-四氯二苯并-对二恶英）和内源性化合物（例如色氨酸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成为癌症和其他疾病中免疫抑制的关键、多方面调节剂，其中许多功能是由 Kyn 介导的，Kyn 是色氨酸降解酶色氨酸-和吲哚胺-2,3- 的可溶性产物。双加氧酶（分别为 TDO 和 IDO）。许多研究将肿瘤进展和临床结果与色氨酸分解代谢水平或 IDO 和 TDO 活性相关联。靶向 AhR 通路，而不是 IDO（其抑制剂目前正处于癌症 I 期临床试验）或 TDO 最终可能被证明是癌症治疗中更有效且广泛适用的抗免疫抑制策略，可解决两种酶促途径的免疫抑制作用。在本提案中，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 拮抗剂的控释纳米颗粒和微粒的局部递送来纵向评估 AhR 在肿瘤建立和肿瘤相关免疫抑制中的作用机制，2) 测试 AhR 拮抗剂作为在化疗和免疫治疗干预背景下增强宿主抗肿瘤免疫力的范例。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影响。