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

项目总结/摘要 癌症免疫疗法已经成为一种革命性的抗肿瘤治疗，并被批准用于治疗过多的癌症。 癌症类型。然而，在实体瘤中，反应有限，只有大约20%的肿瘤细胞具有抗肿瘤活性。 缓解的患者，但肿瘤负荷高的患者除外（通过微卫星不稳定性（MSI）证明） 错配修复缺陷（MMRD）。这种有限的反应对于前列腺癌尤其明显。在 前列腺癌，目前唯一批准的治疗（MSI/MMRD患者除外）是sipuleucel-T， 树突状细胞疫苗Sipuleucel-T在再输注前离体激活抗原呈递细胞， B和T细胞应答的激活与对治疗的应答相关。这种免疫原性骨髓 和淋巴细胞的相互作用只是众多相互作用的一个例子， 或致耐受性。对髓样区室在促肿瘤或抗肿瘤活性中作用的更好理解将 允许在联合免疫治疗策略中改善骨髓区室的靶向。 在外周和肿瘤微环境中都可以观察到免疫抑制性骨髓状态。 免疫系统的外周监测具有令人难以置信的潜力，这是由于监测的容易性和 纵向重复取样的能力。描述循环髓系细胞的异质性， 在一个小隔间里，我使用了一种遗传多重策略，同时分析基因和蛋白质的表达， 纵向采样的约700，000个外周血单核细胞（PBMC）中的单细胞 转移性去势抵抗性前列腺癌（mCRPC）队列接受联合治疗， 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新的骨髓细胞状态， 并研究哪些状态在肿瘤微环境中重演，哪些状态预测 对免疫疗法的临床反应。在我的第二个目标中，我将研究这些髓样细胞是如何 与淋巴区室相互作用以产生免疫原性或致耐受性肿瘤应答。我的担保人， 博士Jimmie Ye，在单细胞组学方面拥有丰富的专业知识，用于分析自动和自动免疫系统， 免疫和肿瘤环境。我的共同赞助人，劳伦斯·方博士，在 癌症免疫治疗领域，特别关注癌症反应背后的机制 泌尿生殖系统癌症的免疫治疗，包括前列腺癌。我的共同赞助人马修·斯皮策博士 在理解免疫系统对肿瘤的全身反应方面具有广泛的专业知识， 特别关注使用质谱细胞术进行高维单细胞蛋白质表达谱分析。我将 正在接受癌症免疫治疗的纵向临床培训， 癌症免疫治疗项目的负责人总的来说，这项工作将奠定基础，提高 预测对癌症免疫治疗的反应和鉴定髓样靶点内的新靶点 以改善实体瘤的临床反应。

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.