Targeting immune suppressive microenvironment in ATC

针对 ATC 中的免疫抑制微环境

• 批准号: 10333316
• 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/10333316
• 关键词: Affect; Antigen Presentation; Antigen Presentation Pathway; Antigens; Attenuated; BRAF gene; Cells; Chromatin Remodeling Factor; Cytotoxic Chemotherapy; DNA Sequence Alteration; Disease; Distant Metastasis; Genetic; Genetic Suppression; Growth; Human; Immune; Immune Targeting; Immunologic Surveillance; Immunologics; Immunosuppression; Individual; Infiltration; Leukocytes; MAP Kinase Gene; MEKs; 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; Pharmacology; Phenocopy; Play; Population; Process; Production; Prognosis; Property; Radiation; Regulation; Regulatory Pathway; Repression; Role; Signal Transduction; T cell response; T-Lymphocyte; TERT gene; TP53 gene; Testing; Therapeutic; Thyroid Gland; Time; Tumor-Derived; Tumor-associated macrophages; Up-Regulation; anaplastic thyroid cancer; base; cancer cell; chemotherapy; cytokine; cytotoxic; cytotoxicity; human disease; immune checkpoint blockade; in vivo; inducible gene expression; inhibitor; macrophage; monocyte; mortality; mouse model; mutant; neoantigens; neoplastic cell; older patient; 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.

项目概要/摘要 甲状腺未分化癌 (ATC) 患者的中位生存期为 6 个月。化疗在 手术和放疗相结合可能会适度延长局限于颈部的 ATC 的生存期，但 对转移性疾病患者的益处微乎其微。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 (Trametinib) 在 BRAFV600E 中显示出 69% 的 ORR 和显着的肿瘤消退 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 同样的组合在 BRAF 驱动的分化型甲状腺癌 (DTC) 中的发病率为 33%。非凡的 dab/tram BRAF-ATC 的影响为探索该疾病的治疗漏洞提供了路线图。一个标志 ATC 的主要特点是它们被具有 M2 极化的肿瘤相关巨噬细胞 (TAM) 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 免疫监视。尽管 ATC 也富含 T 细胞，但免疫检查点封锁的试点试验 (ICB) 在这种疾病中没有显示出疗效，包括在两个具有微卫星不稳定性的 ATC 中，预计 含有大量新抗原。基于我们开发的 Braf 驱动 ATC 的小鼠模型， 概括了人类疾病的免疫环境，我们提出深刻的 MAPK 通路抑制 阻断肿瘤衍生细胞因子的产生，这些细胞因子负责 TAM 的募集和维持，从而导致其 耗竭以及随之而来的 T 细胞细胞毒性的去抑制。我们假设 MAPK 阻断 主要解释了这种 TME 反应，以及 TAM 和 MAPK 对 ATC 抗原呈递的调节 在此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 ATC 细胞衍生的细胞因子，这些细胞因子可招募浸润性骨髓细胞群。我们确定了一个 MAPK- BRAF-ATC 中驱动的细胞因子组，将确定个体细胞因子对骨髓募集的贡献 使用遗传和药理学方法。 2) 确定 TAM 在治疗反应中的作用。我们将 首先研究 TAM 是否会阻断体内 ATC 中 T 细胞对模型抗原（Pmel 和/或 Tyrp1）的反应。 我们将对 TAM 进行遗传或药理学耗竭，以确定增强 T 的最佳方法 细胞反应，然后确定 TAM 耗竭或复极化对 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。 3） 确定 MAPK 抑制后肿瘤细胞抗原呈递在 T 细胞反应中的作用以及是否 Pd1 阻断可以增强反应的幅度或持续时间。 4) 确定顺序变化 人类 BRAFV600E ATC 对术前使用 dab/tram 治疗的免疫状况 在 dab/tram 与 PD1 抑制剂 Cemiplimab 的联合试验中。