Discovery of myeloid immune features predictive of response to cancer immunotherapy in prostate cancer

项目摘要/摘要 癌症免疫疗法是一种革命性的抗肿瘤疗法，已被批准用于治疗过多的 癌症类型。然而，在实体肿瘤中，反应有限，只有大约20% 除了微卫星不稳定性(MSI)所证明的高肿瘤负担的患者外，其他患者均有反应 或错配修复缺陷(MMRD)。这种有限的反应在前列腺癌中尤为明显。在……里面 前列腺癌，目前唯一被批准的治疗方法(除MSI/MMRD患者外)是西普鲁尔-T，一种 树突状细胞疫苗。西普鲁尔-T在体内回输前体外激活抗原提呈细胞 B细胞和T细胞反应的激活与治疗反应有关。这种免疫原性髓系 淋巴细胞的相互作用只是众多相互作用的一个例子，这些相互作用可以是免疫原性的 或者是耐受性。更好地理解髓系隔室在促或抗肿瘤活性中的作用将 在联合免疫治疗策略中，允许改进对髓系间室的靶向。 免疫抑制髓系状态可在肿瘤周围和肿瘤微环境中观察到。 免疫系统的外周监测具有令人难以置信的潜力，因为监测和 能够进行纵向重复采样。表征循环髓系细胞的异质性 时，我使用了一种遗传多重策略来同时分析基因和蛋白质的表达 纵向采样~70万个外周血单核细胞的研究 接受联合治疗的转移性去势抵抗前列腺癌(MCRPC)队列 免疫疗法。在我的第一个目标中，我建议使用这个数据集来描述 并研究哪些状态在肿瘤微环境中重现以及哪些状态可预测 免疫治疗的临床反应。在我的第二个目标中，我将研究这些髓系细胞是如何 与淋巴室相互作用，产生免疫原性或耐受性肿瘤反应。我的赞助人， 吉米·叶博士在单细胞组学方面拥有丰富的专业知识，可以在两种情况下描绘免疫系统- 免疫和肿瘤背景。我的共同赞助人，Lawrence Fong博士，在 癌症免疫治疗领域，特别关注癌症反应背后的机制 包括前列腺癌在内的泌尿生殖系肿瘤的免疫治疗。我的联合赞助人马修·斯皮策博士 在了解免疫系统对肿瘤的全身反应方面具有广泛的专业知识 特别关注使用质量细胞术进行高维单细胞蛋白质表达谱分析。我会的 与主任Lawrence Fong博士一起接受癌症免疫治疗的纵向临床培训 加州大学旧金山分校的癌症免疫治疗项目。总体而言，这项工作将为改进奠定基础 肿瘤免疫治疗反应的预测和髓系靶点新靶点的确定 提高实体瘤的临床疗效。

PROJECT SUMMARY/ABSTRACT Cancer immunotherapy has been a revolutionary antitumor treatment and is approved to treat a plethora of cancer types. However, in solid tumors the response has been limited with only approximately 20 percent of patients responding except for patients with high tumor burden as evidenced by microsatellite instability (MSI) or mismatch repair deficiency (MMRD). The limited response is especially pronounced for prostate cancer. In prostate cancer, the only currently approved therapy (except for MSI/MMRD patients) is sipuleucel-T, a dendritic cell vaccine. Sipuleucel-T activates antigen presenting cells ex vivo before reinfusion where in vivo activation of B and T cell responses are associated with response to the therapy. This immunogenic myeloid and lymphoid cell interaction is just one example of a plethora of interactions which can be either immunogenic or tolerogenic. Improved understanding of the role of myeloid compartment in pro- or anti-tumor activity will allow for improved targeting of the myeloid compartment in combination immunotherapy strategies. Immunosuppressive myeloid states can be observed both in the periphery and in the tumor microenvironment. Peripheral monitoring of the immune system holds incredible potential due to the ease of monitoring and the ability for longitudinal repeated sampling. To characterize the heterogeneity of the circulating myeloid compartment, I used a genetic multiplexing strategy to simultaneously profile gene and protein expression on single cells from ~700,000 peripheral blood mononuclear cells (PBMCs) from longitudinal sampling of a metastatic castration resistant prostate cancer (mCRPC) cohort undergoing combined immunotherapy. In my first aim, I propose to use this dataset to describe novel myeloid cell states in the periphery and to investigate which states recapitulate in the tumor microenvironment and which states predict clinical response to the immunotherapy. In my second aim, I will investigate how these myeloid cell states interact with the lymphoid compartment to create an immunogenic or tolerogenic tumor response. My sponsor, Dr. Jimmie Ye, has extensive expertise in single cell –omics for profiling the immune system in both auto- immune and tumor contexts. My co-sponsor, Dr. Lawrence Fong, has made foundational discoveries in the field of cancer immunotherapy with a particular focused on the mechanisms behind response to cancer immunotherapy in genitourinary cancers, including prostate cancer. My co-sponsor, Dr. Matthew Spitzer, has extensive expertise in the understanding the systemic response of the immune system to a tumor with a particular focus in using mass cytometry for high dimensional single cell protein expression profiling. I will be undergoing longitudinal clinical training in cancer immunotherapy with Dr. Lawrence Fong, who is the director of the Cancer Immunotherapy Program at UCSF. Overall, this work will lay the foundation for improved prediction of response to cancer immunotherapy and the identification of novel targets within the myeloid target to improve clinical response in solid tumors.