Identifying and targeting a novel mechanism of chemotherapy-induced immunotherapeutic resistance in non-small cell lung cancer

识别和靶向非小细胞肺癌化疗引起的免疫治疗耐药的新机制

• 批准号: 10657188
• 负责人: Kavitha Yaddanapudi
• 金额: $ 35.33万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10657188
• 关键词: Address; Adenosine; Attenuated; CD8-Positive T-Lymphocytes; Cancer Model; Cancer Patient; Carboplatin; Cell physiology; Cells; Cisplatin; Clinical; Combination immunotherapy; Combined Modality Therapy; Cytotoxic agent; Data; Dinoprostone; Disease; Effectiveness; Energy-Generating Resources; Enzymes; Epithelial Cells; Eragrostis; FDA approved; Generations; Glucose; Health; Human; Immune; Immune Evasion; Immune checkpoint inhibitor; Immune response; Immune system; Immuno-Chemotherapy; Immunosuppression; Immunotherapeutic agent; Immunotherapy; Inosine; KRASG12D; Life; Lung; Malignant neoplasm of lung; Mediating; Metabolic; Modeling; Molecular; Monoclonal Antibodies; Mus; Myeloid Cells; Myeloid-derived suppressor cells; Non-Small-Cell Lung Carcinoma; Nucleotidases; Nutrient; Outcome; PTGS2 gene; Paracrine Communication; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Polyethylene Glycols; Polyunsaturated Fatty Acids; Production; Purine Nucleosides; Recombinants; Relapse; Resistance; Risk; Sampling; Signal Induction; Signal Pathway; Surface; System; T-Lymphocyte; Testing; Therapeutic; Transgenic Mice; Translating; Treatment Failure; Treatment Protocols; Tumor Immunity; United States; Up-Regulation; Xenograft procedure; adenosine deaminase; anti-PD-1; anti-PD1 antibodies; cancer cell; cancer therapy; cancer type; chemotherapy; clinically relevant; effectiveness testing; effector T cell; extracellular; human disease; humanized mouse; immunogenic cell death; improved; in vivo; innovation; monocyte; mortality; mouse model; neoplastic cell; novel; novel therapeutic intervention; patient derived xenograft model; programmed cell death ligand 1; programmed cell death protein 1; randomized, clinical trials; response; standard of care; therapy resistant; tumor; tumor ablation; tumor microenvironment; tumor-immune system interactions

Lung cancer kills more people than any other type of cancer, including more than 130,000 people each year in the United States. Non-small cell lung cancer (NSCLC) is the most common subtype (82% of all lung cancers) and can arise from squamous or non-squamous lung epithelial cells. Combination treatment with immunotherapy (i.e., monoclonal antibodies targeted to PD-1 or PD-L1) plus concurrent chemotherapy (usually including cisplatin or carboplatin) is now part of the standard of care for many patients with NSCLC. Although in lab-based studies, chemotherapy has some effects that are expected to enhance the efficacy of immunotherapies, whether chemotherapy can also have paradoxical negative effects that diminish immunotherapy efficacy is not well understood at present. Based on our preliminary data, we propose to investigate how cisplatin, a chemotherapy commonly used to treat NSCLC, creates an immunosuppressive tumor microenvironment (TME) that limits the anti-tumor activity of anti-PD-1 immunotherapy. Specifically, we hypothesize the following steps: (a) cisplatin induces prostaglandin E2 (PGE2) production in tumor cells; (b) PGE2 leads to upregulation of CD73 enzyme on the surface of monocytic myeloid-derived suppressor cells (M-MDSCs); (c) CD73 catalyzes the production of extracellular adenosine from AMP (derived from ATP released from dying cells); and (d) adenosine inhibits the activation of effector T cells within the tumor microenvironment (TME) and thus limits the efficacy of chemo- immunotherapy. Furthermore, we propose a novel therapeutic strategy for overcoming this adenosine-mediated immunosuppression and sensitizing tumors to chemo-immunotherapy, whereby co-treatment with recombinant polyethylene glycol-conjugated adenosine deaminase enzyme (PEG-ADA) will convert immunosuppressive adenosine into immunostimulatory inosine. In Specific Aim 1 of this project, we will test our predictions about the key cellular and molecular players in this pathway, including cisplatin-induced PGE2 secretion, CD73 expression on M-MDSC, adenosine production and suppression of anti-tumoral T cell activity. We will use a variety of in vivo systems that provide a faithful representation of human NSCLC, including an orthotopic murine lung cancer model and humanized mice with patient-derived xenografts (PDX). In Specific Aim 2, we will test the effectiveness of selectively deleting CD73 in M-MDSCs or co-treating with PEG-ADA as approaches to increase the anti-tumor/immunostimulatory activities of chemo-immunotherapy (anti-PD-1 + cisplatin) in transgenic mouse models of non-squamous and squamous NSCLC. We will also examine tumor samples from NSCLC patients who have progressed on anti-PD-1/chemotherapy for correlative evidence of this novel mechanism. Completion of these aims will identify novel and actionable immunosuppressive mechanisms that mediate relapse and therapeutic resistance in metastatic NSCLC patients. Our studies will establish adding PEG-ADA (a drug that is FDA-approved for a non-cancer indication) to standard chemo-immunotherapy as a promising strategy that can be quickly translated into improved NSCLC treatment regimens.

肺癌杀死的人比其他任何类型的癌症都多，包括每年超过130,000人 美国。非小细胞肺癌（NSCLC）是最常见的亚型（所有肺癌的82％） 并且可能是由鳞状或非肺肺上皮细胞引起的。与免疫疗法的联合治疗 （即针对PD-1或PD-L1的单克隆抗体）加上并发化疗（通常包括顺铂 对于许多NSCLC患者而言，Carboplatin）现在已成为护理标准的一部分。虽然在基于实验室的研究中 化学疗法的某些作用有望增强免疫疗法的功效，是否是否 化学疗法也可能具有矛盾的负面影响，即降低免疫疗法的功效不好 目前了解。根据我们的初步数据，我们建议研究顺铂如何（一种化学疗法） 通常用于治疗NSCLC，创建一种免疫抑制肿瘤微环境（TME），该微环境限制了 抗PD-1免疫疗法的抗肿瘤活性。具体而言，我们假设以下步骤：（a）顺铂 在肿瘤细胞中诱导前列腺素E2（PGE2）产生； （b）PGE2导致CD73酶的上调 单核细胞衍生的抑制细胞（M-MDSC）的表面； （c）CD73催化生产 来自AMP的细胞外腺苷（源自垂死细胞释放的ATP）； （d）腺苷抑制 肿瘤微环境（TME）中效应T细胞的激活，因此限制了化学的功效 免疫疗法。此外，我们提出了一种克服这种腺苷介导的新型治疗策略 免疫抑制和敏感性肿瘤对化学免疫疗法，从而与重组共同治疗 聚乙烯乙二醇偶联的腺苷脱氨酶（PEG-ADA）将转换免疫抑制 腺苷成免疫刺激内因。在该项目的特定目的1中，我们将测试有关该项目的预测 该途径中的关键细胞和分子玩家，包括顺铂诱导的PGE2分泌，CD73表达 在M-MDSC上，腺苷产生和抗肿瘤T细胞活性的抑制。我们将使用各种体内 提供人类NSCLC的忠实表示的系统，包括原位鼠肺癌 具有患者衍生异种移植物（PDX）的模型和人源化小鼠。在特定目标2中，我们将测试 选择性删除M-MDSC中CD73或与PEG-ADA共处的有效性 转基因小鼠中化学免疫疗法（抗PD-1 +顺铂）的抗肿瘤/免疫刺激活性 非质量和鳞状NSCLC的模型。我们还将检查NSCLC患者的肿瘤样品 他们在抗PD-1/化学疗法上进行了这种新机制的相关证据。完成 这些目的将确定介导复发和可行的新型免疫抑制机制 转移性NSCLC患者的治疗性抗性。我们的研究将建立添加PEG-ADA（一种药物 FDA批准用于非癌症指示）标准化学免疫疗法是一种有前途的策略 快速转化为改进的NSCLC治疗方案。