Naive T cells in Cancer Immune Evasion and Immunotherapy

初始 T 细胞在癌症免疫逃避和免疫治疗中的应用

• 批准号: 10411383
• 负责人: WEIPING ZOU
• 金额: $ 8.1万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10411383
• 关键词: Advanced Malignant Neoplasm; Affect; Antigen Targeting; Antigen-Presenting Cells; Antitumor Response; Apoptosis; Autophagocytosis; Cancer Remission; Cell physiology; Clinical; Clinical Trials; Dendritic Cells; Environment; FOXP3 gene; Failure; Functional disorder; Heterogeneity; Homeostasis; Human; Immune; Immune response; Immunotherapeutic agent; Immunotherapy; Impairment; Malignant Neoplasms; Malignant neoplasm of ovary; Mediating; Memory; Metabolic; Molecular; Mus; Myeloid-derived suppressor cells; Nature; PD-1 blockade; PD-1 pathway; Pathway interactions; Patients; Phenotype; Regulation; Regulatory T-Lymphocyte; T cell differentiation; T memory cell; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic; Time; Tumor Antigens; Tumor Escape; Tumor Immunity; Tumor-infiltrating immune cells; cancer immunotherapy; cancer type; checkpoint therapy; clinical application; draining lymph node; effector T cell; exhaust; lymph nodes; lymphoid structures; malformation; mouse model; patient subsets; peripheral blood; programmed cell death ligand 1; programmed cell death protein 1; receptor; response; targeted treatment; tumor; tumor metabolism; tumor microenvironment

T cells are the main effector components of anti-tumor immunity in the majority of cancer types. The phenotypic and functional heterogeneity of memory T cells in the human cancer environment have been the focus of recent studies. We and others have shown that the metabolic alteration in the cancer microenvironment can directly mediate memory and effector T cell dysfunction. However, it is unknown whether naïve T cells are targeted and altered by cancer metabolism in patients with cancer, particularly in patients with advanced cancer. PD-L1 and PD-1 blockade and other types of checkpoint therapy target, rescue, and promote effector T cell function to achieve clinical response. However, it is unknown if and how naïve T cells are involved in the current cancer immunotherapy-mediated mechanisms. There is a balanced loss and replacement of naïve T cells in the periphery. The molecular basis of naïve T cell quiescence has been studied in homeostasis in mice. However, the nature of naïve T cells is poorly defined in patients with cancer and in tumor bearing mouse models under homeostatic situation and immunotherapeutic settings. Alteration of naïve T cells may likely affect T cell homeostasis and memory T cell differentiation and functionality in the tumor bearing hosts. Thus, it is time to systemically study the nature of naïve T cells in tumor bearing hosts. In the current proposal, we will investigate the functional and molecular features and therapeutic relevance of naïve T cells in patients with ovarian cancer and in several tumor bearing mouse models. Our specific aims are: Aim 1 is to test our hypothesis that autophagy malformation is a molecular feature of naïve T cells in tumor. Aim 2 is to determine the molecular mechanisms of FIP200 loss in naïve T cells in tumor. Aim 3 is to test our hypothesis that FIP200 in naïve T cells affects spontaneous and therapy-induced tumor immunity.

T细胞是大多数癌症类型中抗肿瘤免疫的主要效应成分。的 在人类癌症环境中记忆T细胞的表型和功能异质性一直是 近期研究的重点。我们和其他人已经证明癌症中的代谢改变 微环境可以直接介导记忆和效应T细胞功能障碍。但不清楚 在癌症患者中，初始T细胞是否被癌症代谢靶向和改变，特别是在 晚期癌症患者。 PD-L1和PD-1阻断和其他类型的检查点疗法靶向、拯救和促进效应T细胞 以达到临床反应。然而，目前尚不清楚幼稚T细胞是否以及如何参与免疫应答。 目前癌症免疫治疗介导的机制。 在外周中存在幼稚T细胞的平衡损失和替代。幼稚T细胞的分子基础 已经在小鼠体内稳态中研究了静止。然而，幼稚T细胞的性质在免疫学中定义不清。 肿瘤患者和荷瘤小鼠模型在稳态和免疫状态下 设置.幼稚T细胞的改变可能影响T细胞稳态和记忆T细胞分化， 在肿瘤承载宿主中的功能性。因此，是时候系统地研究幼稚T细胞的性质了， 携带肿瘤的宿主。在目前的提案中，我们将研究功能和分子特征， 卵巢癌患者和几种荷瘤小鼠中幼稚T细胞的治疗相关性 模型我们的具体目标是： 目的1是验证我们的假设，即自噬畸形是肿瘤中幼稚T细胞的分子特征。 目的二是探讨肿瘤中幼稚T细胞FIP 200缺失的分子机制。 目的3是验证我们的假设，即幼稚T细胞中的FIP 200影响自发性和治疗诱导的肿瘤 免疫力

项目成果

IFNα Augments Clinical Efficacy of Regulatory T-cell Depletion with Denileukin Diftitox in Ovarian Cancer.

IFNα 增强了 Denileukin Diftitox 消除卵巢癌调节性 T 细胞的临床疗效。

• DOI: 10.1158/1078-0432.ccr-20-4594
• 发表时间: 2021
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Thibodeaux,SuzanneR;Barnett,BrianB;Pandeswara,Srilakshmi;Wall,ShawnaR;Hurez,Vincent;Dao,Vinh;Sun,Lishi;Daniel,BenjaminJ;Brumlik,MichaelJ;Drerup,Justin;Padrón,Álvaro;Whiteside,Teresa;Kryczek,Ilona;Zou,Weiping;Curiel,Tyler
• 通讯作者: Curiel,Tyler