NCAM1 potentiates small cell lung cancer stemness and resistance to NK cell-mediated cytotoxicity

Intrinsic resistance of small cell lung cancer (SCLC) to immunotherapy underscores our limited understanding of how tumors can evade immune responses. Here we demonstrated that neural cell adhesion molecule 1 (NCAM1, also called CD56) facilitates disease progression, tumor stemness, and resistance to NK cell-mediated cytotoxicity in SCLC. Mechanistically, cis-binding of NCAM1 with its ligand L1CAM on the surface of identical tumor cell occupied considerable antigenic epitopes of L1CAM, and thereby prevented L1CAM from trans-binding with CD56+ NK cells to form immune-synapse structures, which may render the tumor cells more resistant to NK cell-mediated cytotoxicity in SCLC. Additionally, CHMP4B, a member of the ESCRT complex involved in plasma membrane repair, were essential for SCLC stemness and NK cell-mediated cytotoxicity, and NCAM1 can protect SCLC cells from immune attack and stem cell renewal by interacting with CHMP4B. SCLC specimens with concurrent high expression of NCAM1 and CHMP4B exhibited lower cytotoxic immune cell infiltration, were located farther from cytotoxic immune cells, and were associated with inferior clinical outcomes. These findings reveal potential mechanisms of NCAM1 in sustaining SCLC stemness and resisting cytolytic attack, and provide a potential target of CHMP4B against self-renewal and immunoresistance.