Molecular and immune drivers of immunotherapy responsiveness in prostate cancer

项目总结 尽管最近在治疗方面取得了进展，但转移性去势抵抗前列腺癌(MCRPC)仍然存在 无法治愈，每年约有30,000人死于这种疾病。药物免疫治疗的研究进展 针对免疫检查点的研究带来了希望，即这些药物将改善mCRPC的结果 病人。虽然对免疫检查点封锁的初步研究一直不成功，但新的证据表明 提示前列腺癌(PCA)患者的一部分可以做出反应，尽管PCA的机制 免疫治疗的反应和耐药性尚不完全清楚。在其他免疫疗法中工作 反应性恶性肿瘤已经发现了几种预测性免疫和肿瘤固有特性，这些特性有助于 但这些(或其他)特征在PCA中起作用的程度在很大程度上是未知的。为 例如，我们最近发现了介导免疫治疗的染色质重塑复合体的突变。 实体瘤中T细胞相互作用的应答，同时发现了一种以前未知的PCA 由这些相同染色质重构体的突变所定义的基因组亚类。这些发现表明， 肿瘤固有的表观遗传失调也可能与免疫系统相互作用来调节前列腺癌 免疫治疗的反应性。这个项目的首要假设是多重免疫和肿瘤- 内在属性调节PCA与免疫系统的相互作用，这些相互作用是可以修改的 通过选择性靶向与关卡封锁相结合的方式，扩大对脑出血的治疗潜力 免疫治疗在前列腺癌中的应用。我们将利用我们团队在临床基础分子方面的丰富经验 特征和临床前模型，可以测试PCA中的免疫治疗组合以确定 在PCA中管理免疫治疗前景的过程。建议的具体目标是：1)界定 PCa的全身和浸润性免疫状态与临床对检查点封锁的反应有关；2) 建立染色质失调和抑制对PCa的免疫学影响；以及3)确定 现有DNA损伤剂对PD-1阻滞剂增敏前列腺癌的影响。这项提议充分利用了 达纳-法伯/布罗德学院和华盛顿大学的广泛、新颖和互补的资源 加州，旧金山，在高度合作的调查人员和国际科学团队的领导下， 解决这里概述的假设。通过功能、分子和临床的组合 这些研究中固有的方法，我们的团队准备确定可能从中受益的mCRPC队列 治疗范例，确定在这种疾病中增加检查点抑制剂使用的策略，以及 从机制上定义了在前列腺癌中驱动免疫抵抗的免疫和肿瘤固有缺陷。大体上， 该项目将为免疫肿瘤学翻译网络(IOTN)社区提供一种独特的方法 并使发现可能具有更大相关性的PCA的抗癌免疫疗法策略成为可能 通过IOTN网络和癌症免疫治疗联盟的合作成员。

PROJECT SUMMARY Despite recent advances in treatment, metastatic castration resistant prostate cancer (mCRPC) remains incurable, and approximately 30,000 men die of this disease yearly. Advances in immunotherapy with drugs targeting immune checkpoints have raised hopes that these agents will improve outcomes for mCRPC patients. While initial studies of immune checkpoint blockade have been unsuccessful, emerging evidence suggests a subset of prostate cancer (PCa) patients can respond, although the mechanisms of PCa immunotherapy response and resistance are incompletely characterized. Work in other immunotherapy responsive malignancies has found several predictive immune and tumor-intrinsic properties that contribute to response, but the extent to which these (or other) features are operant in PCa is largely unknown. For example, we recently identified mutations in a chromatin remodeling complex that mediates immunotherapy response through T cell interactions in solid tumors, and in parallel discovered a previously unknown PCa genomic subclass defined by mutations in these same chromatin remodelers. These findings indicate that tumor-intrinsic epigenetic dysregulation may also interact with the immune system to modulate PCa immunotherapy responsiveness. The overarching hypothesis of this project is that multiple immune and tumor- intrinsic properties mediate PCa interactions with the immune system, and these interactions can be modified through selective targeting in combination with checkpoint blockade to expand the therapeutic potential of immunotherapy in PCa. We will leverage our team's deep experience in clinically grounded molecular characterization and preclinical models that can test immunotherapy combinations in PCa to define the processes that govern the immunotherapy landscape in PCa. The proposed specific aims are: 1) Define the systemic and infiltrating immune states in PCa associated with clinical response to checkpoint blockade; 2) Establish the immunologic impact of chromatin dysregulation and inhibition in PCa; and 3) Determine the impact of existing DNA damaging agents for sensitizing PCa to PD-1 blockade. This proposal leverages the extensive, novel, and complementary resources at both Dana-Farber/Broad Institute and University of California, San Francisco, led by highly collaborative investigators and an international scientific team, to address the hypotheses outlined herein. Through a combination of functional, molecular, and clinical approaches inherent in these studies, our team is poised to identify mCRPC cohorts that may benefit from this treatment paradigm, determine strategies to augment the use of checkpoint inhibitors in this disease, and mechanistically define the immune and tumor-intrinsic defects that drive immunoresistance in PCa. Broadly, this project will provide a unique approach for the Immuno-Oncology Translation Network (IOTN) community and enable discovery of anti-cancer immunotherapies strategies for PCa that may have larger relevance across the IOTN network and collaborating members of the Cancer Immunotherapy Consortium.