Elucidating the Contextual Roles of IL-10 in Patient Response to Cancer Immunotherapy

阐明 IL-10 在患者对癌症免疫治疗反应中的背景作用

• 批准号: 10408837
• 负责人: David Michael Woods
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10408837
• 关键词: Address; Adoptive Cell Transfers; Aftercare; Anti-Inflammatory Agents; Antibodies; Antigen-Presenting Cells; Antigens; Antitumor Response; Bioinformatics; Biological Markers; Blocking Antibodies; Cell Culture Techniques; Cell physiology; Cells; Clinical; Cytotoxic T-Lymphocytes; Data; Development; Development Plans; Ensure; Equine mule; Evaluation; Grant; Health; Immune; Immune Targeting; Immune response; Immunosuppression; Immunotherapy; In Vitro; Incidence; Inflammatory; Interleukin-10; Literature; Malignant Neoplasms; Manuscripts; Mediating; Memory; Mentors; Metastatic Melanoma; Modeling; Myeloid Cells; Myeloid-derived suppressor cells; Nivolumab; PD-1 blockade; Patient-Focused Outcomes; Patients; Peripheral Blood Mononuclear Cell; Phase; Play; Population; Pre-Clinical Model; Production; Publishing; Recording of previous events; Regulatory T-Lymphocyte; Research; Research Personnel; Research Proposals; Resources; Role; STAT3 gene; Serum; Source; T-Lymphocyte; Techniques; Testing; Training; Tumor Immunity; United States; Writing; anergy; antagonist; anti-PD-1; base; bench to bedside; cancer immunotherapy; career; career development; checkpoint therapy; cytokine; effector T cell; efficacy testing; experience; high dimensionality; immune checkpoint blockade; immune function; improved; melanoma; mouse model; novel; novel strategies; patient biomarkers; patient response; pembrolizumab; pleiotropism; pre-clinical; programmed cell death protein 1; receptor; research and development; resistance mechanism; response; single-cell RNA sequencing; success; targeted delivery; targeted treatment; tumor; tumor immunology

Project Summary/Abstract Recently therapies targeting the immune response, such as PD1 antagonists, have demonstrated unprecedented success in the treatment of metastatic melanoma. However, with the majority of patients failing to respond, there is a need for an understanding of the mechanisms of resistance and novel approaches to improve immunotherapies. This proposal seeks to address that need by investigating the roles of IL-10 in patient response to immunotherapy. Preliminary data demonstrate that patients responding to PD1 blockade had increased T-cell STAT3 and IL10 expression, which was absent in non-responding patients. In vitro, treatment of T-cell cultures with αPD1 resulted in STAT3 dependent increases in IL-10 production. Treatment of T-cells with exogenous IL-10 enhanced T-cell cytolytic functions, proliferation, memory and rescues anergic cells. These effects were enhanced when combined with αPD1. However, IL10 treatment of total PBMC resulted in increased M2-like antigen presenting cells and myeloid derived suppressor cells, and in turn decreased T-cell effector functions. Based on these and published studies, we hypothesize that IL-10 induction is a biomarker of patient response to PD1 blockade therapy and that T-cell targeted delivery of IL-10 can enhance PD1 blockade immunotherapy. To address this hypothesis, the proposed research will investigate 1) changes in the production of IL-10 by different patient immune cell populations after PD1 blockade and the relation to patient outcome, 2) the mechanisms by which αPD1 induces T-cell IL-10 production, 3) the mechanisms by which IL-10 has cytolytic promoting effects on T-cells and opposing effects in the presence of antigen presenting cells, 4) the ability of IL- 10 to enhance adoptive cell therapy in preclinical murine models, and 5) to test the efficacy of T-cell targeted delivery by an αPD1/IL-10 conjugate to enhance immunotherapy. These lines of research will be addressed throughout the K99 phase of this grant and continue during the R00 phase. This research stands to have significant clinical impact through demonstrating novel mechanisms through which αPD1 therapies function and improving patient responses by rationale combinations. In addition, this grant outlines my career development plan for obtaining the requisite training necessary to be a productive and successful independent academic researcher. This includes mentoring by Dr. Jeffrey Weber and Dr. Pratip Chattopadhyay and a Scientific Advisory & Career Development Committee consisting of Dr. Itai Yanai, Dr. Kwok-Kin Wong and Dr. James Mulé. As part of my plan, I will take coursework in bioinformatics, grant writing and managing a lab. I will also train in techniques including single cell RNA-Seq, high dimension flow cytometery and murine models of adoptive cell therapy. The labs of Dr. Weber and Dr. Chattopadhyay and NYU Health will provide the resources critical to my training and to the proposed research, ensuring my success. Collectively, the proposed career development and research plans are expected to generate data with significant impact on the treatment of metastatic melanoma while propelling my career and setting the theme of my lab as an independent researcher.

项目摘要/摘要 最近针对免疫反应的疗法，如PD1拮抗剂，已经证明 在治疗转移性黑色素瘤方面取得前所未有的成功。然而，随着大多数患者的失败 为了应对，有必要了解耐药性的机制，并采取新的方法来应对 改进免疫疗法。这项建议试图通过研究IL-10在患者中的作用来满足这一需求 对免疫治疗的反应。初步数据显示，对PD1阻断有反应的患者有 T细胞STAT3和IL10表达增加，这在无应答患者中是不存在的。在体外，治疗 与αPD1共同培养的T细胞可导致依赖STAT3的IL-10产生增加。T细胞的治疗 外源性IL-10可增强T细胞的溶细胞功能，促进增殖、记忆和拯救无能细胞。这些 当与αPD1联合使用时，效果更佳。然而，IL10处理的总PBMC导致增加 M2样抗原提呈细胞和髓系来源的抑制细胞，进而减少T细胞效应器 功能。基于这些和已发表的研究，我们假设IL-10的诱导是患者的一个生物标志物。 PD1阻断治疗的反应及T细胞靶向传递IL-10可增强PD1的阻断作用 免疫疗法。为了解决这一假设，拟议的研究将调查1)生产的变化 PD1阻断后不同患者免疫细胞群对IL-10的影响及其与预后的关系 αPD1诱导T细胞产生IL-10的机制；3)IL-10的细胞溶解机制 抗原提呈细胞对T细胞的促进作用和对抗作用，4)IL-1 10)加强临床前小鼠模型的过继细胞治疗，5)测试T细胞靶向治疗的效果 由αPD1/IL-10结合物提供，以加强免疫治疗。这些研究路线将被处理 在这笔赠款的K99阶段，并在R00阶段继续。这项研究将会有 通过展示αPD1疗法发挥作用的新机制和 通过合理的组合改善患者的反应。此外，这笔助学金还概述了我的职业发展 计划获得必要的培训，以成为一名富有成效和成功的独立学者 研究员。这包括杰弗里·韦伯博士和普拉提普·查托帕迪耶博士的指导和科学咨询 由柳井正博士、黄国健博士和詹姆士·穆莱博士组成的职业发展委员会。作为一部分 在我的计划中，我将学习生物信息学的课程，撰写拨款和管理一个实验室。我还将接受技术培训 包括单细胞RNA-Seq、高维流式细胞术和过继细胞治疗的小鼠模型。这个 Weber博士和Chattopadhyay博士的实验室以及纽约大学健康学院将提供对我的培训和 对提议的研究，确保了我的成功。总的来说，拟议的职业发展和研究 预计计划将产生对转移性黑色素瘤治疗具有重大影响的数据，而 作为一名独立研究员，推动了我的事业，并确立了我实验室的主题。

项目成果

Clinical and immune correlate results from a phase 1b study of the histone deacetylase inhibitor mocetinostat with ipilimumab and nivolumab in unresectable stage III/IV melanoma.

• DOI: 10.1097/cmr.0000000000000818
• 发表时间: 2022-10-01
• 期刊: MELANOMA RESEARCH
• 影响因子: 2.2
• 作者: Weber, Jeffrey S.;Levinson, Benjamin A.;Laino, Andressa S.;Pavlick, Anna C.;Woods, David M.
• 通讯作者: Woods, David M.

CD4 Phenotypes Are Associated with Reduced Expansion of Tumor-Infiltrating Lymphocytes in Melanoma Patients Treated with Adoptive Cell Therapy.

CD4 表型与接受过继细胞疗法治疗的黑色素瘤患者肿瘤浸润淋巴细胞扩增减少相关。

• DOI: 10.4049/jimmunol.2300250
• 发表时间: 2023
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Thompson,Brian;Strange,Ann;Amato,CarolM;Hester-McCullough,Jonathan;Sarnaik,AmodA;Weber,JeffreyS;Woods,DavidM
• 通讯作者: Woods,DavidM