PO.IM01.05 · 免疫学
靶向小细胞肺癌神经内分泌亚型的CADM1-CAR T细胞
CADM1-CAR T cells targeting neuroendocrine subtypes of small cell lung cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
小细胞肺癌（SCLC）约占所有肺癌病例的15%，是一种以快速增殖、早期播散和治疗耐药性发展为特征的侵袭性癌症。近期的转录组学分析根据谱系特化转录因子ASCL1、NEUROD1、YAP1和POU2F3的表达，将SCLC划分为不同的分子亚型。其中，神经内分泌亚型SCLC-A（ASCL1驱动）和SCLC-N（NEUROD1驱动）在80%的患者群体中占主导地位。由于主要组织相容性复合体（MHC）分子的内在低表达以及由此导致的对免疫检查点阻断的应答不佳，开发不依赖MHC的免疫治疗策略对SCLC至关重要。细胞黏附分子1（CADM1）是一种具有情境依赖性肿瘤抑制和促肿瘤功能的膜糖蛋白，在SCLC中异常表达，并参与调控细胞黏附、免疫逃逸和转移播散。我们的分析显示，CADM1表达与MHC表达评分呈负相关，并在具有高神经内分泌分化（ASCL1和NEUROD1主导亚型）的初治肿瘤中富集。肿瘤细胞中CADM1的过表达使其成为抗原特异性免疫治疗的一个有吸引力的靶点。为利用这一脆弱性，我们工程化构建了一种CADM1特异性嵌合抗原受体（CADM1-CAR）T细胞。CADM1-CAR T细胞表现出强健的抗原依赖性细胞毒性、增强的效应细胞因子分泌（IFN-gamma、TNF-alpha）以及溶细胞介质（granzyme A/B、穿孔素）的上调，从而在体外产生强效的SCLC细胞裂解。在携带播散性H82异种移植瘤的NSG小鼠中，CADM1-CAR T细胞治疗显著抑制了肿瘤进展并延长了总生存期。这些发现确立了CADM1作为一种有前景的肿瘤相关抗原，并支持CADM1靶向CAR-T细胞疗法治疗高级别神经内分泌SCLC的治疗潜力。
查看英文原文 English abstract
Small cell lung cancer (SCLC), accounting for approximately 15% of all lung cancer cases, represents an aggressive carcinoma characterized by rapid proliferation, early dissemination, and the development of therapeutic resistance. Recent transcriptomic profiling has delineated SCLC into distinct molecular subtypes defined by the expression of lineage-specifying transcription factors ASCL1, NEUROD1, YAP1, and POU2F3. Among these, the neuroendocrine subtypes SCLC-A (ASCL1-driven) and SCLC-N (NEUROD1-driven) predominate in 80% of patient populations. Due to the intrinsically low expression of major histocompatibility complex (MHC) molecules and the consequent poor responsiveness to immune checkpoint blockade, the development of MHC-independent immunotherapeutic strategies is imperative for SCLC. Cell Adhesion Molecule 1 (CADM1), a membrane glycoprotein with context-dependent tumor suppressor and pro-tumorigenic functions, is aberrantly expressed in SCLC and implicated in regulating cellular adhesion, immune evasion, and metastatic dissemination. Our analyses revealed that CADM1 expression inversely correlates with MHC expression scores and is enriched in treatment-naïve tumors with high neuroendocrine differentiation (ASCL1- and NEUROD1-dominant subtypes). The overexpression of CADM1 in tumor cells, makes it an attractive target for antigen-specific immunotherapy. To exploit this vulnerability, we engineered a CADM1-specific chimeric antigen receptor (CADM1-CAR) T cell. CADM1-CAR T cells exhibited robust antigen-dependent cytotoxicity, enhanced secretion of effector cytokines (IFN-gamma, TNF-alpha), and upregulation of cytolytic mediators (granzyme A/B, perforin), resulting in potent SCLC cell lysis in vitro. In NSG mice bearing disseminated H82 xenografts, CADM1-CAR T cell treatment significantly inhibited tumor progression and extended overall survival. These findings establish CADM1 as a promising tumor-associated antigen and support the therapeutic potential of CADM1-targeted CAR T cell therapy for high-grade neuroendocrine SCLC.
利益披露 Disclosure
S. Katkam, None..
S. Chuikov, None..
Z. Wang, None.