Cell adhesion molecule-1 is a promising target for chimeric antigen receptors in lung adenocarcinoma

Abstract

Advances in targeted therapies, immune-checkpoint inhibitors, and chemo-immunotherapy combinations have improved survival in subsets of lung adenocarcinoma (LUAD) patients, yet novel treatments are needed for those who do not respond. We previously demonstrated that Cell Adhesion Molecule 1 (CADM1) is modulated by EMT-MET cycling in lung cancer cells, and mediates NK-mediated immune surveillance. In this study, CADM1 expression was confirmed on the cell surface, correlating with poor survival in LUAD patients, identifying it as a potential therapeutic target for chimeric antigen receptor (CAR) based approach. An anti-CADM1 chimeric antigen receptor (CAR) was developed, demonstrating robust CADM1-specific activity against lung cancer cells. CADM1-CAR-T cells exhibited a balanced composition of stem cell-like (T_SCM), central memory (T_CM), along with effector memory (T_EM), and effector (T_EFF) T cells, crucial for immediate and sustained tumor eradication. In NSG mouse models with orthotopic LUAD xenografts, CADM1-CAR-T cells inhibited tumor growth and extended survival compared to controls, with no effect on CADM1-negative xenografts. Interestingly, CADM1-CAR-T cells did not inhibit subcutaneous tumor growth but effectively reduced spontaneous metastases, underscoring their potential in metastatic LUAD. These findings establish CADM1 as a new target for CAR-T therapies, highlighting its promise for treating both primary and metastatic LUAD.