• We emphasized the potential critical role of CD58 loss in resistance to CAR T-cell therapy.

  • Loss of CD58 caused inefficient IS formation with CAR T cells, impairing the activation and cytotoxic function of CAR T cells.

Chimeric antigen receptor (CAR) T-cell therapy has achieved significant success in treating a variety of hematologic malignancies, but resistance to this treatment in some patients limited its wider application. Using an unbiased genome-wide CRISPR/Cas9 screening, we identified and validated loss of CD58 conferred immune evasion from CAR T cells in vitro and in vivo. CD58 is a ligand of the T cell costimulatory molecule CD2, and CD58 mutation or downregulated expression is common in hematological tumors. We found that disruption of CD58 in tumor cells induced the formation of suboptimal immunological synapse (IS) with CAR T cells, which conferred functional impairment of CAR T cells, including the attenuation of cell expansion, degranulation, cytokine secretion and cytotoxicity. In summary, we describe a potential mechanism of tumor intrinsic resistance to CAR T-cell therapy and suggest that this mechanism may be leveraged for developing therapeutic strategies to overcome resistance to CAR T-cell therapy in B-cell malignancies.

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