Targeting immune suppressive microenvironment in ATC

针对 ATC 中的免疫抑制微环境

• 批准号: 10559692
• 负责人: JAMES A FAGIN
• 金额: $ 43.19万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10559692
• 关键词: Affect; Antigen Presentation; Antigen Presentation Pathway; Antigen-Presenting Cells; Antigens; Attenuated; BRAF gene; Cells; Chromatin Remodeling Factor; Combined Modality Therapy; Cytotoxic Chemotherapy; DNA Sequence Alteration; Disease; Distant Metastasis; Genes; Genetic; Genetic Suppression; Growth; Human; Immune; Immune Targeting; Immunologic Surveillance; Immunologics; Immunosuppression; Individual; Infiltration; Leukocytes; MAP Kinase Gene; MEKs; Macrophage; Maintenance; Malignant Neoplasms; Malignant neoplasm of thyroid; Microsatellite Instability; Modeling; Mus; Mutation; Myelogenous; Myeloid Cells; Myeloid-derived suppressor cells; Neck; Oncogenic; Operative Surgical Procedures; PD-1 blockade; PD-1 inhibitors; Pathway interactions; Patients; Phenocopy; Play; Population; Process; Production; Prognosis; Property; Radiation; Regulation; Regulatory Pathway; Role; Signal Transduction; T cell response; T-Lymphocyte; TP53 gene; Testing; Therapeutic; Thyroid Gland; Tumor-Derived; Tumor-associated macrophages; Up-Regulation; anaplastic thyroid cancer; cancer cell; chemotherapy; cytokine; cytotoxic; cytotoxicity; derepression; human disease; immune checkpoint blockade; in vivo; inducible gene expression; inhibitor; monocyte; mortality; mouse model; mutant; neoantigens; neoplastic cell; older patient; pharmacologic; pilot trial; programs; recruit; resistance mechanism; response; therapy resistant; treatment response; tumor

PROJECT SUMMARY/ABSTRACT Patients with anaplastic thyroid cancer (ATC) have a median survival of 6 months. Chemotherapy in combination with surgery and radiation may modestly extend survival of ATC confined to the neck but offers minimal benefit in patients with metastatic disease. Recently, combination treatment using the RAF inhibitor dabrafenib with the MEK inhibitor trametinib showed a 69% ORR and dramatic tumor regression in BRAFV600E- driven ATCs, which is the first meaningful advance in the treatment of this disease. In contrast, response to this same combination in BRAF-driven differentiated thyroid cancer (DTC) is 33%. The remarkable dab/tram effects in BRAF-ATCs provide a roadmap to explore the therapeutic vulnerabilities in this disease. A hallmark of ATCs is their heavy infiltration with tumor-associated macrophages (TAMs) with M2 polarization. TAMs are associated with a worse prognosis in thyroid and other cancers, attributed in part to their suppression of immune surveillance. Although ATCs are also enriched for T cells, a pilot trial of immune checkpoint blockade (ICB) showed no efficacy in this disease, including in two ATCs with microsatellite-instability, predicted to harbor numerous neoantigens. Based on a mouse model of Braf-driven ATC that we developed, which recapitulates the immune milieu of the human disease, we propose that profound MAPK pathway inhibition blocks production of tumor-derived cytokines governing TAM recruitment and maintenance, leading to their depletion and the consequent de-repression of T cell cytotoxicity. We hypothesize that MAPK blockade primarily accounts for this TME response, and that TAMs and MAPK regulation of ATC antigen presentation play a central role in the process. To understand the relative contribution of these mechanisms we will: 1) Identify ATC cell-derived cytokines that recruit infiltrating myeloid cell populations. We identified a MAPK- driven cytokine panel in BRAF-ATCs and will determine individual cytokine contributions to myeloid recruitment using genetic and pharmacological approaches. 2) Determine the role of TAMs in response to therapy. We will first investigate whether TAMs block T-cell responses to model antigens (Pmel and/or Tyrp1) in ATCs in vivo. We will perform genetic or pharmacological depletion of TAMs to determine the optimal approach to enhance T cell responses, then determine the effects of TAM depletion or repolarization on T cell response to tumor cell autonomous neoantigens, and whether these can further enhance efficacy of ICB in mouse Braf/p53 ATCs. 3) Determine the role of tumor cell antigen presentation in T cell response following MAPK inhibition and whether the magnitude or duration of response can be enhanced by Pd1 blockade. 4) Determine sequential changes in the immune landscape of human BRAFV600E ATCs in response to preoperative treatment with dab/tram and during a combination trial of dab/tram with the PD1 inhibitor Cemiplimab.

项目总结/摘要 甲状腺未分化癌（ATC）患者的中位生存期为6个月。化疗 结合手术和放射治疗可能会适度延长仅限于颈部的ATC的生存期， 转移性疾病患者获益甚微。最近，使用RAF抑制剂的联合治疗 达拉非尼与MEK抑制剂曲美替尼在BRAFV 600 E-1中显示69%的ORR和显著的肿瘤消退。 驱动的ATC，这是治疗这种疾病的第一个有意义的进展。相反，响应 在BRAF驱动的分化型甲状腺癌（DTC）中，这种相同的组合是33%。非凡的DAB/电车 BRAF-ATC中的作用提供了探索这种疾病的治疗弱点的路线图。一个标志 ATC的最大特征是它们与具有M2极化的肿瘤相关巨噬细胞（TAM）的严重浸润。TAM是 与甲状腺癌和其他癌症的预后较差有关，部分原因是它们抑制了甲状腺癌和其他癌症的预后。 免疫监视尽管ATC也富含T细胞，但免疫检查点阻断的试点试验 (ICB)在这种疾病中没有表现出疗效，包括在两个具有微卫星不稳定性的ATC中， 含有许多新抗原。基于我们开发的Braf驱动的ATC小鼠模型， 概括了人类疾病的免疫环境，我们提出，深刻的MAPK通路抑制 阻断肿瘤源性细胞因子的产生，控制TAM的募集和维持， 消耗和随后的T细胞细胞毒性的去抑制。我们假设阻断MAPK TME反应的主要原因是TAMs和MAPK对ATC抗原呈递的调节 在这个过程中发挥核心作用。为了了解这些机制的相对贡献，我们将：1） 鉴定招募浸润性骨髓细胞群的ATC细胞源性细胞因子。我们发现了一种MAPK- 在BRAF-ATC中驱动细胞因子面板，并将确定单个细胞因子对骨髓募集的贡献 使用遗传学和药理学方法。2)确定TAM在治疗反应中的作用。我们将 首先研究TAM是否在体内阻断ATC中T细胞对模型抗原（Pmel和/或Tyrp 1）的应答。 我们将对TAM进行遗传或药理学耗竭，以确定增强T细胞增殖的最佳方法。 细胞反应，然后确定TAM耗尽或复极化对T细胞对肿瘤细胞反应的影响 自主新抗原，以及这些是否可以进一步增强ICB在小鼠Braf/p53 ATC中的功效。第三章 确定MAPK抑制后肿瘤细胞抗原呈递在T细胞应答中的作用， 反应的幅度或持续时间可通过Pd 1阻断而增强。4)确定以下方面的顺序变化 人BRAFV 600 E ATC响应于用dab/tram的术前治疗的免疫状况， 在dab/tram与PD 1抑制剂Cemiplimab的联合试验期间。