Immunesurveillance of Lung Cancer by Natural Killer Cells

自然杀伤细胞对肺癌的免疫监视

• 批准号: 10623168
• 负责人: Venkateshwar G Keshamouni
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-10-01 至 2025-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10623168
• 关键词: Activated Natural Killer Cell; Adhesives; Binding; Calcium; Cancer Etiology; Cancer Patient; Cell Adhesion Inhibition; Cell Adhesion Molecules; Cell Line; Cell Surface Proteins; Cell physiology; Cells; Clinical; Data; Disease; Disease Progression; Enzyme Inhibition; Epithelium; Genetic; Host Defense; Human; Hypermethylation; Immune Evasion; Immune system; Immunoglobulins; Immunologic Surveillance; Immunotherapy; Incidence; Infiltration; Ligands; Loss of Heterozygosity; LoxP-flanked allele; Lung; Lung Neoplasms; Lymphoid Cell; MHC Class I Genes; Malignant Neoplasms; Malignant neoplasm of lung; Mammals; Mediating; Mesenchymal; Modification; Mus; NCAM1 gene; Natural Killer Cells; Neoplasm Metastasis; Nodal; Non-Small-Cell Lung Carcinoma; Patients; Polysialic Acid; Population; Predisposition; Property; Proteins; Regulation; Role; Sialyltransferases; Smoking; T-Lymphocyte; Toxic effect; Tumor Burden; Tumor Promotion; Tumor Tissue; United States; Veterans; Virus Diseases; Woman; cancer cell; cancer immunotherapy; cancer risk; carbohydrate structure; class-I restricted T cell-associated molecule; cohort; cytotoxicity; design; effective therapy; efficacy testing; glycosylation; immune checkpoint blockade; immunological synapse; in vitro activity; men; mortality; mouse model; mutant; neoplastic cell; novel; patient prognosis; peripheral blood; prevent; programmed cell death ligand 1; promoter; synthetic biology; therapeutically effective; tumor; tumor initiation; tumor progression; tumorigenesis

Immunesurveillance of Lung Cancer by Natural Killer Cells Abstract Lung cancer is the leading cause of cancer related mortality in both men and women in the United States. Non-small cell lung cancer (NSCLC) constitutes 80% of all lung cancers and immune checkpoint blockade has emerged as an effective therapeutic strategy, but only 20% of NSCLC patients respond to these agents. Among veterans both the rate of incidence and the rate of mortality are twice higher than the entire population, making this an urgent unmet clinical need among veterans particularly for those who do not respond to current therapies. NK cells are innate lymphoid cells fundamental to host defense against viral infections and malignancies. In humans, low NK cell cytotoxicity in peripheral blood correlates with increased cancer risk. Conversely, NK cell infiltration into tumor tissue is associated with better patient prognosis in multiple malignancies, including NSCLC. Our preliminary data show that depletion of NK cells in a genetic mouse model of lung cancer significantly promotes tumor progression, increases tumor burden and decreases survival of mice, demonstrating a critical role for NK-mediated immune surveillance in lung tumorogenesis Cell adhesion molecule 1 (CADM1) belongs to the immunoglobulin superfamily of calcium independent cell adhesion molecules, capable of both homophilic and heterophilic interactions. Interestingly, CADM1 expression is frequently lost in 20-40% of non-small cell lung cancers (NSCLC) either by loss of heterozygosity or promoter hypermethylation. However, the mechanism(s) by which CADM1 regulates tumor progression is not known. CADM1 is one of seven proteins in mammals that undergoes an unusual glycosylation known as polysialylation. The other notable Polysialic acid (polysia) carrier is the protein CD56 expressed on NK cells. Polysia is a unique carbohydrate structure known for its potent anti-adhesive properties preventing two polysialylated proteins from interacting with each other. On the other hand, a cell surface protein known as CRTAM (Class-I MHC-restricted T-cell-associated molecule) was identified as the strongest heterophilic binding partner of CADM1. CRTAM is expressed on activated NK cells and the CADM1/CRTAM axis has been implicated in immune surveillance. Our recent study showed that, in cells expressing CADM1, its induction renders cancer cells susceptible to NK-mediated cytotoxicity. Inhibition of CADM1 expression promoted metastasis by evading NK mediated immune surveillance. In contrast, restoring CADM1 in cells with promoter hypermethylation was sufficient to make cancer cells susceptible to NK-mediated toxicity, suggesting that suppressing CADM1 may be an immune evasive strategy of tumors. Consistently, increased expression of CADM1 directly correlated with prolonged patient survival and inversely correlated with higher stage and metastatic disease. We show that polysialylation of CADM1 on tumor cells modulates their susceptibility to NK cells. Based on these observations, we hypothesize that CADM1 mediates an immunological synapse between tumor cells and NK cells promoting tumor immune surveillance and its function is regulated by a unique glycosylation modification. Strategies to enhance CADM1-mediated NK surveillance may be an effective immunotherapy against NSCLC, particularly for tumors that are CADM1 positive. The three specific aims of this project are: 1) Define the role of CADM1 in the regulation of lung tumor progression. 2) Determine the mechanism(s) by which CADM1 function is regulated to modulate tumor immunosurveillance 3) Design and develop CADM1 targeting CAR-NK cells for lung cancer immunotherapy.

自然杀伤细胞对肺癌的免疫监测 摘要 肺癌是美国男性和女性癌症相关死亡率的主要原因。 非小细胞肺癌（NSCLC）占所有肺癌的80%，免疫检查点阻断具有重要意义。 作为一种有效的治疗策略，但只有20%的NSCLC患者对这些药物有反应。之间 退伍军人无论是发病率还是死亡率都比整个人群高出一倍，使得 这是退伍军人中迫切的未满足的临床需求，特别是对于那些对当前疗法没有反应的人。 NK细胞是宿主防御病毒感染和恶性肿瘤的基本先天淋巴细胞。 在人类中，外周血中的低NK细胞毒性与癌症风险增加相关。NK细胞 在多种恶性肿瘤中，浸润到肿瘤组织中与更好的患者预后相关，包括 NSCLC。我们的初步数据显示，在肺癌遗传小鼠模型中，NK细胞的耗竭 显著促进肿瘤进展，增加肿瘤负荷并降低小鼠存活率，表明 NK介导的免疫监视在肺肿瘤发生中的关键作用 细胞粘附分子1（CADM 1）属于免疫球蛋白超家族， 细胞粘附分子，能够同嗜性和异嗜性相互作用。有趣的是，CADM 1 在20-40%的非小细胞肺癌（NSCLC）中， 或启动子超甲基化。然而，CADM 1调节肿瘤进展的机制并不重要。 知道的CADM 1是哺乳动物中经历不寻常糖基化的七种蛋白质之一， 聚唾液酸化另一个值得注意的聚唾液酸（polysia）载体是NK细胞上表达的蛋白质CD 56。 Polysia是一种独特的碳水化合物结构，以其有效的抗粘附特性而闻名， 多聚唾液酸化蛋白质相互作用。另一方面，一种被称为 CRTAM（I类MHC限制性T细胞相关分子）被鉴定为最强的嗜异性结合 CADM 1的合作伙伴。CRTAM在活化的NK细胞上表达，并且CADM 1/CRTAM轴已经被证实是一种新的细胞因子。 与免疫监视有关。 我们最近的研究表明，在表达CADM 1的细胞中，它的诱导使癌细胞易感 NK介导的细胞毒性。抑制CADM 1表达通过逃避NK介导的转移促进肿瘤转移 免疫监视相反，在启动子高甲基化的细胞中恢复CADM 1足以 使癌细胞对NK介导的毒性敏感，这表明抑制CADM 1可能是一种免疫抑制剂。 肿瘤的逃避策略一致地，CADM 1表达增加直接相关于 患者存活率与较高分期和转移性疾病呈负相关。我们发现聚唾液酸化 肿瘤细胞上的CADM 1调节其对NK细胞的易感性。根据这些观察，我们 假设CADM 1介导肿瘤细胞和NK细胞之间的免疫突触， 肿瘤免疫监视及其功能受独特的糖基化修饰调节。的战略 增强CADM 1介导的NK监视可能是针对NSCLC的有效免疫疗法，特别是对于 CADM 1阳性的肿瘤。该项目的三个具体目标是：1）确定CADM 1在 调节肺肿瘤进展。2)确定调节CADM 1功能的机制， 调节肿瘤免疫监视3）设计和开发针对肺癌的CADM 1靶向CAR-NK细胞 免疫疗法