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.

肺癌导致的死亡人数比任何其他类型的癌症都多，其中每年有超过13万人死于肺癌 美国。非小细胞肺癌(NSCLC)是最常见的亚型(占所有肺癌的82%) 可由鳞状上皮或非鳞状上皮细胞产生。联合治疗与免疫治疗 (即，针对PD-1或PD-L1的单抗)加同期化疗(通常包括顺铂 或卡铂)现在是许多非小细胞肺癌患者标准治疗的一部分。尽管在基于实验室的研究中， 化疗有一些效果，有望增强免疫疗法的疗效，无论 化疗还会产生矛盾的负面影响，即降低免疫治疗的效果 据目前所知。基于我们的初步数据，我们建议研究顺铂，一种化疗药物 通常用于治疗NSCLC，创建免疫抑制的肿瘤微环境(TME)，限制 抗PD-1免疫治疗的抗肿瘤活性。具体来说，我们假设以下步骤：(A)顺铂 诱导肿瘤细胞产生前列腺素E2(PGE2)；(B)PGE2导致CD73酶上调 单核细胞髓系衍生抑制细胞(M-MDSCs)表面；(C)CD73催化产生 来自AMP的胞外腺苷(来自垂死细胞释放的ATP)；和(D)腺苷抑制 在肿瘤微环境(TME)内激活效应T细胞，从而限制化疗的疗效。 免疫疗法。此外，我们提出了一种新的治疗策略来克服这种腺苷介导的 免疫抑制和使肿瘤对化学免疫治疗增敏，从而与重组人 聚乙二醇偶联腺苷脱氨酶(PEGADA)将免疫抑制转化为 腺苷转化为免疫刺激性肌苷。在这个项目的具体目标1中，我们将测试我们对 这一途径中的关键细胞和分子参与者，包括顺铂诱导的PGE2分泌，CD73的表达 对M-MDSC、腺苷的产生和抗肿瘤T细胞活性的抑制。我们将在体内使用各种各样的 提供真实的人类非小细胞肺癌代表的系统，包括原位小鼠肺癌 使用患者来源的异种移植物(PDX)建立模型并人源化小鼠。在具体目标2中，我们将测试 选择性删除M-MDSCs中CD73或与聚乙二醇腺嘌呤二核苷酸共处理作为提高疗效的途径 化疗免疫疗法(抗PD-1+顺铂)在转基因小鼠中的抗肿瘤/免疫刺激活性 非鳞状和鳞状非小细胞肺癌模型。我们还将检查非小细胞肺癌患者的肿瘤样本。 他们在抗PD-1/化疗方面取得了进展，为这一新机制提供了相关证据。完成 这些目标将确定新的和可操作的免疫抑制机制，介导复发和 转移性非小细胞肺癌患者的治疗耐药性。我们的研究将确定添加聚乙二醇-ADA(一种药物 FDA批准的非癌症适应症)将标准的化学免疫疗法作为一种有希望的策略，可以 迅速转化为改进的非小细胞肺癌治疗方案。