Cell adhesion molecule ITGB2 promotes CAR-T cell therapy in B-cell malignancies

CAR-T cell therapy, as a representative technology in cancer immunotherapy, has demonstrated notable success in the treatment of hematologic malignancies; however, a significant proportion of patients fail to achieve sustained remission. Through the analysis of bone marrow sequencing data prior to CD19 CAR-T cell therapy, we identified cellular adhesion as a pivotal factor influencing clinical outcomes. We developed a model to predict B-ALL treatment efficacy based on the core genes associated with cellular adhesion, which was validated in our clinical cohort. Both in vitro and in vivo experiments revealed that the inhibition or knockout of integrin subunit beta 2 (ITGB2, also known as CD18) in malignant B cells markedly diminished the cytotoxic efficacy of both CD19 and CD20 CAR-T cells against B-lineage tumor cells, with alterations in ITGB2-mediated cytotoxicity linked to the formation of immunological synapses within the tumor microenvironment. Notably, the upregulation of ITGB2 in Nalm6 cells via LPS or Venetoclax significantly augmented the cytotoxic activity of CAR-T cells against Nalm6 cells. Our findings provide a novel predictive model for clinical CD19 CAR-T cell therapy and elucidate a role of the ITGB2 pathway in CAR-T cell-mediated eradication of B-cell malignancies.