Targeting immune suppressive microenvironment in ATC

项目摘要/摘要 间变性甲状腺癌(ATC)患者的中位生存期为6个月。在中国进行化疗 结合手术和放疗可能会适度延长局限于颈部的ATC的生存时间，但提供了 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 使用MEK抑制剂曲美替尼的达普拉非尼在BRAFV600E中显示69%的ORR和显著的肿瘤消退。 这是治疗这种疾病的第一个有意义的进展。相比之下，对以下问题的回应 在BRAF驱动的分化型甲状腺癌(DTC)中，这一组合的比例为33%。引人注目的轻轨/有轨电车 对BRAF-ATCs的影响为探索这种疾病的治疗脆弱性提供了路线图。一个标志性的 ATCs的特点是大量的肿瘤相关巨噬细胞(TAMs)，伴有M2极化。TAMS是 与甲状腺和其他癌症预后较差有关，部分原因是它们抑制了 免疫监视。尽管ATCs也富含T细胞，但免疫检查点阻断的试点试验 (ICB)对这种疾病没有疗效，包括对两个具有微卫星不稳定的ATC，预计 蕴藏着大量的新抗原。基于我们开发的BRAF驱动的ATC小鼠模型，该模型 概述了人类疾病的免疫环境，我们提出了深刻的MAPK通路抑制 阻断控制招募和维持的肿瘤衍生细胞因子的产生，导致其 耗竭和随之而来的T细胞细胞毒性的降低。我们假设MAPK封锁 主要解释了这种TME反应，以及TAMS和MAPK对ATC抗原提呈的调节 在这一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) 识别ATC细胞衍生的细胞因子，以招募浸润性髓系细胞群。我们确认了一个MAPK- BRAF-ATCs中的驱动细胞因子小组，并将确定单个细胞因子对髓系募集的贡献 使用遗传和药理学方法。2)确定TAMS在治疗反应中的作用。我们会 首先，研究TAMS是否在体内阻断了ATCs对模型抗原(PMEL和/或Tyrp1)的T细胞反应。 我们将进行TAMs的遗传或药物耗竭，以确定增强T细胞的最佳方法 细胞反应，然后确定耗尽或复极化对T细胞对肿瘤细胞反应的影响 自主新抗原，以及这些新抗原是否能进一步增强ICB对小鼠BRAF/P53 ATCs的疗效。3) 确定肿瘤细胞抗原提呈在MAPK抑制后T细胞反应中的作用以及 PD1封锁可以提高反应的幅度或持续时间。4)确定以下项目的顺序更改 人BRAFV600E ATCs对术前应用DAB/TRAM和 在DAB/TRAM与PD1抑制剂Cymplimab的联合试验中。

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.