Mechanisms of resistance to immune therapy in NSCLC

NSCLC 免疫治疗耐药机制

基本信息

批准号：
10333209
负责人：
Qingsheng Li
金额：
$ 26.99万
依托单位：
UNIVERSITY OF LOUISVILLE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10333209
关键词：
Address Bioinformatics Biopsy Specimen CD3 Antigens CD8-Positive T-Lymphocytes CD8B1 gene Cancer Center Cancer Model Cancer Patient Cells Clinic Clinical Data Disease FDA approved Failure Generations Germ-Free Goals Grant Growth Human IL17 gene Immune checkpoint inhibitor Immunity Immunotherapy Individual Interleukin-17 KRASG12D Lung Lung Adenocarcinoma Lung Neoplasms Lymphocyte Lymphocyte Activation Macrophage Activation Malignant neoplasm of lung Mediating Mus Neoadjuvant Therapy Non-Small-Cell Lung Carcinoma Operative Surgical Procedures Patients Production Progression-Free Survivals Psoriasis Resistance Severities Specimen T-Cell Activation T-Lymphocyte Testing Therapeutic anti-PD-1 anti-PD1 antibodies anti-PD1 therapy base cancer immunotherapy checkpoint therapy clinically relevant commensal bacteria cytotoxic cytotoxicity design human microbiota in vivo interstitial lung microbiota lymphoid neoplasm macrophage microbiota microbiota profiles mouse model neoantigens neoplastic neutralizing antibody novel predict responsiveness prognostic programmed cell death protein 1 prospective resistance factors resistance mechanism response restoration standard of care therapy outcome tumor tumor immunology tumorigenic γδ T cells

项目摘要

ABSTRACT Despite having been approved as first and second line therapy for non-small cell lung cancer (NSCLC), anti-PD- 1 antibodies still fail in a substantial proportion of lung cancer patients. The mechanism that underlies the failure of anti-PD-1 therapy in the majority of NSCLC patients is not yet fully understood. We have discovered that, in the anti-PD-1-resistant LSL-KrasG12D murine lung adenocarcinoma mouse model, treatment induces a T-cell activation profile that favors Th17/γδT17 reinvigoration over CD8+ T cell activation. In contrast, when administered in conjunction with an anti-IL-17 neutralizing antibody, anti-PD-1 treatment results in a dramatic enhancement of CD8+ T-cell cytotoxicity with near-complete eradication of established disease. These findings provide the premise for our central hypothesis that in NSCLC, the failure of anti-PD-1 is, at least in part, due to reinvigoration of PD-1+ type 17 T cells (Th17/γδT17), which actively undermine anti-PD-1-mediated restoration of cytotoxic function in CD8+ T-cells. Based on additional murine data, we are also advancing the extended hypothesis that the severity of pre-existing T17 activity in the neoplastic lung is determined by commensal bacteria and that the lung microbiota signature can ultimately predict responsiveness to anti-PD-1 therapy. The goal of this proposal is to demonstrate the relevance of these findings to human prior to initiating an R01 application. Specifically, in Aim 1, we will establish whether intrinsic lung T17/CTL ratio is predictive of anti-PD- 1 responsiveness in NSCLC patients independent of neoantigen burden. In Aim 2 we will determine whether specific human lung microbiota, individually or in defined combinations, drive the ontogeny of intrinsic T17 immunity and ultimately resistance to ICI therapy. The proposed study is conceptually impactful as it addresses an important clinical conundrum; is mechanistically novel; and has translational relevance since it introduces therapeutic/prognostic approaches that can rapidly move to the clinic.

抽象的尽管已被批准作为非小细胞肺癌 (NSCLC) 的一线和二线疗法，抗 PD- 1 抗体在相当大比例的肺癌患者中仍然失败。失败的机制。我们发现，大多数 NSCLC 患者中抗 PD-1 治疗的效果尚未完全了解。抗PD-1耐药LSL-KrasG12D鼠肺腺癌小鼠模型，诱导T细胞治疗相反，当 CD8+ T 细胞激活时，有利于 Th17/γδT17 重振。与抗 IL-17 中和抗体联合使用，抗 PD-1 治疗效果显着这些发现增强了 CD8+ T 细胞的细胞毒性，几乎完全根除既定疾病。为我们的中心假设提供了前提，即在 NSCLC 中，抗 PD-1 的失败至少部分是由于 PD-1+ 17 型 T 细胞 (Th17/γδT17) 的重振，积极破坏抗 PD-1 介导的恢复基于其他小鼠数据，我们还在推进扩展的 CD8+ T 细胞的细胞毒性功能。假设肿瘤性肺中预先存在的 T17 活性的严重程度是由共生决定的细菌以及肺部微生物群特征最终可以预测对抗 PD-1 治疗的反应。该提案的目标是在启动 R01 之前证明这些发现与人类的相关性具体来说，在目标 1 中，我们将确定内在肺 T17/CTL 比率是否可以预测抗 PD-。 1 NSCLC 患者的反应性与新抗原负荷无关。在目标 2 中，我们将确定是否存在这种情况。特定的人类肺部微生物群，单独或以特定的组合，驱动内在 T17 的个体发育免疫和最终对 ICI 治疗的抵抗力拟议的研究在概念上具有影响力，因为它解决了这一问题。一个重要的临床难题；在机制上是新颖的；并且由于它引入了翻译相关性；可以快速转移到临床的治疗/预后方法。