Integrin β6-Targeted CAR-T Cells exhibit potent antitumor activity in β6-Positive pancreatic ductal adenocarcinoma and lung adenocarcinoma

Abstract

Pancreatic ductal adenocarcinoma (PDAC) and lung adenocarcinoma (LUAD) remain lethal malignancies with limited therapeutic options, highlighting an urgent need for more effective treatments. Integrin αvβ6 (ITGB6) is a receptor preferentially expressed in specific types of tumors, such as PDAC and LUAD, and represents a promising yet largely untapped target for cellular immunotherapy. We aimed to develop and preclinically validate a novel chimeric antigen receptor T-cell (CAR-T) therapy targeting ITGB6 for these aggressive solid tumors. A third-generation anti-ITGB6 CAR was designed and constructed, incorporating both CD28 and TLR2 co-stimulatory domains. TLR2 signaling enhances T-cell expansion, cytokine production, and infiltration into solid tumor. The potency and specificity of anti-ITGB6 CAR-T cells were assessed against a panel of ITGB6-positive PDAC and LUAD cell lines, patient-derived organoids (PDOs), orthotopic models, and patient-derived xenograft (PDX) models. Anti-ITGB6 CAR-T cells demonstrated potent cytotoxicity against ITGB6-positive PDAC and LUAD models in vitro, effectively targeting both cell lines and PDOs. In murine xenograft models, a single dose of anti-ITGB6 CAR-T cells induced significant tumor suppression and prolonged survival, with no evidence of on-target/off-tumor toxicity was observed. Our findings provide compelling preclinical proof-of-concept for anti-ITGB6 CAR-T therapy as a potent and safe investigational strategy against ITGB6-positive solid tumors, supporting its clinical translation for patients with PDAC and LUAD.