Strategies to predict and overcome resistance to cancer immunotherapy

预测和克服癌症免疫治疗耐药性的策略

基本信息

批准号：
10638167
负责人：
STEVEN L REINER
金额：
$ 54.75万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-01 至 2028-02-29
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10638167
关键词：
Address Antigens Biological Markers Blood Blood Tests Blood specimen CD8-Positive T-Lymphocytes Cancer Patient Cell Differentiation process Cell division Cells Cellular biology Clinical Clinical Trials Clone Cells Confocal Microscopy Consensus Defense Mechanisms Dose Equilibrium Flow Cytometry Frequencies Functional disorder Head and Neck Squamous Cell Carcinoma Image Cytometry Immunity Immunofluorescence Immunologic Immunotherapy Lesion Link Malignant Neoplasms Malignant Squamous Cell Neoplasm Minority Mitotic Morphology Mus Nature Non-Small-Cell Lung Carcinoma Operative Surgical Procedures Output PD-1 blockade PIK3CG gene Patients Peripheral Blood Mononuclear Cell Persons Pharmaceutical Preparations Physiologic pulse Production Proliferating Radiation therapy Resistance Siblings Signal Transduction Sister T cell differentiation T-Cell Activation T-Cell Proliferation T-Lymphocyte Testing Tissues Tumor Immunity Tumor Tissue Work advanced disease anti-PD-1 anti-PD1 therapy anti-cancer blood treatment cancer care cancer immunotherapy cancer type candidate marker cell regeneration chemotherapy clinical practice confocal imaging daughter cell disorder control experimental study immune checkpoint blockade improved in vivo insight kindred novel strategies patient response peripheral blood pre-clinical predictive marker progenitor receptor regenerative response response biomarker self-renewal stem cells stem-like cell translational applications transmission process tumor tumor growth

Address Antigens Biological Markers Blood Blood Tests Blood specimen CD8-Positive T-Lymphocytes Cancer Patient Cell Differentiation process Cell division Cells Cellular biology Clinical Clinical Trials Clone Cells Confocal Microscopy Consensus Defense Mechanisms Dose Equilibrium Flow Cytometry Frequencies Functional disorder Head and Neck Squamous Cell Carcinoma Image Cytometry Immunity Immunofluorescence Immunologic Immunotherapy Lesion Link Malignant Neoplasms Malignant Squamous Cell Neoplasm Minority Mitotic Morphology Mus Nature Non-Small-Cell Lung Carcinoma Operative Surgical Procedures Output PD-1 blockade PIK3CG gene Patients Peripheral Blood Mononuclear Cell Persons Pharmaceutical Preparations Physiologic pulse Production Proliferating Radiation therapy Resistance Siblings Signal Transduction Sister T cell differentiation T-Cell Activation T-Cell Proliferation T-Lymphocyte Testing Tissues Tumor Immunity Tumor Tissue Work advanced disease anti-PD-1 anti-PD1 therapy anti-cancer blood treatment cancer care cancer immunotherapy cancer type candidate marker cell regeneration chemotherapy clinical practice confocal imaging daughter cell disorder control experimental study immune checkpoint blockade improved in vivo insight kindred novel strategies patient response peripheral blood pre-clinical predictive marker progenitor receptor regenerative response response biomarker self-renewal stem cells stem-like cell translational applications transmission process tumor tumor growth

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项目摘要

Immunotherapies such as PD-1 blockade have revolutionized cancer care. Yet most patients do not experience sustained (durable) benefit from blockade of T cell inhibitory receptors. Unfortunately, current biomarkers do not adequately predict patient response or resistance to immunotherapy; and successful strategies to overcome immunotherapy resistance have been lacking. Both gaps reflect our incomplete understanding of how durable immunity carried out by T cells is achieved. Progenitor T cells normally balance the mutually opposing demands of differentiation and self- renewal by transmitting unequal anabolic activating signals to daughter cells. In the setting of cancer, however, sustained T cell activation skews the normal regenerative equilibrium of balanced differentiation and renewal towards progressive dysfunction of differentiated cells along with progressive loss of self-renewing T cells. It was previously presumed that PD-1 blockade acted by restoring potency to the most dysfunctional T cells. Instead, emerging consensus has demonstrated that PD-1 blockade can only function by inducing greater division and differentiation of self- renewing T cells, which are already in peril. This preclinical and translational application marshals our basic discoveries concerning the signaling and cell biology of T cell regeneration to tackle a major clinical roadblock in cancer care. Performing the aims of this proposal will enable determination of 1) whether anti-cancer immunity and immunotherapy impact the self-renewal of CD8+ T cells; 2) whether immunotherapy can be improved by augmenting CD8+ T cell self-renewal; and 3) whether patient response and resistance to immune checkpoint blockade can be predicted from the abundance of self-renewing T cells. This proposal would address two critical unmet patient needs: a non-invasive predictive biomarker for response and resistance to immunotherapy across cancer types; and a novel strategy for resistance-directed treatment enabling immunotherapy to benefit the majority, rather than the minority of patients.

PD-1封锁等免疫疗法彻底改变了癌症护理。然而大多数患者没有受到T细胞阻滞的持续（耐用）受益抑制受体。不幸的是，当前的生物标志物不能充分预测患者对免疫疗法的反应或抵抗力；和成功克服的策略缺乏免疫疗法。两个差距都反映了我们的不完整了解如何实现T细胞进行耐用的免疫力。祖先t 细胞通常平衡相互反对的分化和自我的需求通过向子细胞传输不等的合成代谢激活信号来续订。在然而，癌症的设置持续的T细胞激活偏向正常平衡分化的再生平衡和对渐进式的更新分化细胞的功能障碍以及自我更新T细胞的逐渐丧失。它以前是假定PD-1封锁是通过将效力恢复到最多的功能失调的T细胞。相反，新兴共识证明了PD-1 封锁只能通过诱导更大的分裂和自我分化来发挥作用更新的T细胞已经处于危险之中。这个临床前和翻译应用元帅我们关于T细胞的信号传导和细胞生物学的基本发现再生以应对癌症护理中主要的临床障碍。执行目标该提案将确定1）抗癌免疫和是否是否免疫疗法会影响CD8+ T细胞的自我更新； 2）免疫疗法是否可以通过增强CD8+ T细胞自我更新来改善； 3）患者是否反应可以从丰度中预测对免疫检查点封锁的抵抗力自我更新T细胞。该建议将满足两个关键未满足的患者需求：非侵入性预测性生物标志物，以应对免疫疗法的反应和抗性跨癌症类型；以及一种新型的阻力指导治疗策略免疫疗法使大多数人受益，而不是少数患者。