Mechanisms of resistance to immune therapy in NSCLC

NSCLC 免疫治疗耐药机制

• 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
• 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

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.

摘要 尽管已被批准为非小细胞肺癌(NSCLC)的一线和二线治疗方法，但抗PD- 1抗体在相当大比例的肺癌患者中仍然无效。造成这一失败的机制 抗PD-1治疗在大多数非小细胞肺癌患者中的作用尚不完全清楚。我们发现，在 抗PD-1耐药的LSL-KrasG12D小鼠肺腺癌模型，治疗诱导T细胞 更有利于Th17/γδT17活化而不是CD8+T细胞活化的激活模式。相比之下，当 联合应用抗IL-17中和抗体，抗PD-1治疗效果显著 CD8+T细胞的细胞毒作用随着疾病的近乎完全根除而增强。这些发现 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 主动破坏抗PD-1介导的修复的PD-1+型17 T细胞(Th17/γδT17)的活化 CD8+T细胞的细胞毒作用。基于更多的鼠类数据，我们也在推进扩展的 假设肿瘤肺中先前存在的T17活动的严重程度是由共生关系决定的 细菌和肺微生物区系特征最终可以预测抗PD-1治疗的反应性。这个 这项建议的目标是在启动R01之前证明这些发现与人类的相关性 申请。具体地说，在目标1中，我们将确定肺固有的T17/CTL比率是否预示着抗PD- 1非小细胞肺癌患者的反应性与新抗原负荷无关。在目标2中，我们将确定 特定的人肺微生物区系，单独或以定义的组合，驱动固有的T17的个体发育 免疫，并最终抵抗ICI治疗。拟议的研究在概念上是有影响的，因为它解决了 一个重要的临床难题；从机制上讲是新的；并具有翻译相关性，因为它引入了 可迅速应用于临床的治疗/预后方法。