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

发现可预测前列腺癌癌症免疫治疗反应的骨髓免疫特征

基本信息

批准号：
10540693
负责人：
Elizabeth McCarthy
金额：
$ 5.27万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10540693
关键词：
Address Age Antigen-Presenting Cells Autoimmune B-Cell Activation Cell Communication Cell Compartmentation Cells Clinical Clonality Combination immunotherapy Combined Modality Therapy Complementary DNA Computing Methodologies Cytometry Data Data Set Dendritic Cell Vaccine Development Ethnic Origin Evolution Expression Profiling Foundations Gender Gene Expression Genes Genetic Genetic Transcription Genomics Goals Heterogeneity Immune Immune checkpoint inhibitor Immune response Immune system Immunologic Monitoring Immunologic Stimulation Immunology Immunotherapy Infusion procedures Learning Length Lymphoid Lymphoid Cell Malignant neoplasm of prostate Microsatellite Instability Mismatch Repair Deficiency Modeling Monitor Morbidity - disease rate Multiplexed Ion Beam Imaging Myelogenous Myeloid Cells Oncology Participant Patients Peripheral Peripheral Blood Mononuclear Cell Phenotype Physicians Play Prostate-Specific Antigen Protein Analysis Proteomics Protocols documentation Provenge Role Sampling Scientist Solid Neoplasm T cell response T-Cell Receptor T-Lymphocyte Testing Time Tissue Sample Transcript Tumor Burden Tumor Tissue Urogenital Cancer Work anti-CTLA4 cancer immunotherapy cancer type career castration resistant prostate cancer clinical predictors clinical training clinical trial participant cohort high dimensionality immunogenic improved in vivo ipilimumab method development mortality novel patient subsets predicting response predictive signature programs protein expression response response biomarker single cell proteins skills success targeted treatment tool treatment response tumor tumor microenvironment

项目摘要

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.

项目摘要/摘要癌症Imuntherapy一直是一种革命性的抗肿瘤治疗癌症类型。除肿瘤负担高的患者外，还可以重振患者，这是微卫星不稳定性（MSI）所证明的或不匹配的催化性缺乏（MMRD）前列腺癌，目前唯一经批准的疗法（MSI/MMRD患者除外）是Sipuleucel-T，A 树突状细胞疫苗。 B和T细胞响应的激活与对响应的响应相关淋巴样细胞相互作用只是大量相互作用的一个例子或耐受性的理解。允许在联合免疫疗法策略中改善髓样室的靶向。可以在周围和肿瘤微环境中观察到免疫性髓样状态。免疫系统的外围监测具有令人难以置信的潜力，这是由于易于监测和您纵向重复采样的能力。隔室，i使用遗传多路复用策略同时介绍基因和蛋白质表达从纵向采样的大约700,000个外周血单核细胞（PBMC）的单个细胞上抗性cast割抗性前列腺癌（MCRPC）队列的组合免疫疗法。周围并研究哪种状态在肿瘤微环境中重新资本，哪个国家预测在我的第二个目标中，对免疫疗法的临床反应与淋巴室相互作用，形成免疫原性或耐受性肿瘤反应。 Jimmie Ye博士在单细胞方面拥有广泛的专业知识 - 对两种自动的免疫力进行分析免疫和肿瘤背景。癌症免疫疗法领域，特定于对癌症反应背后的机制 Genitourine癌症的免疫疗法，包括前列腺癌。免疫系统对肿瘤的全身反应的广泛专业知识特别关注质量细胞仪对高维单细胞蛋白表达谱分析。与劳伦斯·方博士（Lawrence Fong UCSF的癌症Imuntherapy计划。预测对癌症免疫疗法的反应和髓样乌龟内新靶的鉴定改善实体瘤的临床反应。