Molecular and immune drivers of immunotherapy responsiveness in prostate cancer

项目摘要 尽管最近在治疗方面取得了进展，但转移性去势抵抗性前列腺癌（mCRPC）仍然存在。 不可治愈，每年约有30，000人死于这种疾病。药物免疫治疗进展 靶向免疫检查点的药物有望改善mCRPC的结局， 患者虽然免疫检查点阻断的初步研究并不成功，但新出现的证据表明， 提示前列腺癌（PCa）患者的一个子集可以响应，虽然PCa的机制， 免疫治疗应答和抗性特征不完全。在其他免疫治疗领域的工作 已经发现了几种预测性免疫和肿瘤内在特性，有助于 反应，但这些（或其他）功能在PCa中的操作性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物的突变 在实体瘤中通过T细胞相互作用的反应，并同时发现了以前未知的PCa 由这些相同染色质重塑物中的突变定义的基因组亚类。这些发现表明 肿瘤内在的表观遗传失调也可能与免疫系统相互作用，调节PCa 免疫治疗反应。该项目的首要假设是，多重免疫和肿瘤- 固有特性介导PCa与免疫系统的相互作用，并且这些相互作用可以被修改 通过选择性靶向结合检查点阻断， 免疫治疗前列腺癌我们将利用我们团队在临床基础分子生物学方面的丰富经验， 表征和临床前模型，可以测试PCa中的免疫治疗组合，以确定 控制PCa免疫治疗前景的过程。建议的具体目标是：（1）确定 与对检查点阻断的临床应答相关的PCa中的全身性和浸润性免疫状态; 2） 建立PCa中染色质失调和抑制的免疫学影响;和3）确定PCa中染色质失调和抑制的免疫学影响。 现有DNA损伤剂对PCa对PD-1阻断剂敏感的影响。该提案利用了 丹娜-法伯/布罗德研究所和牛津大学都有广泛、新颖和互补的资源。 加州，旧金山弗朗西斯科，由高度合作的调查人员和国际科学团队领导， 解决这里概述的假设。通过结合功能性、分子和临床 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，确定增加检查点抑制剂在这种疾病中的使用的策略，以及 机械定义免疫和肿瘤内在缺陷，驱动免疫耐药的PCa。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 并能够发现可能具有更大相关性的PCa抗癌免疫治疗策略 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.