Structural surfaceomics reveals an AML-specific conformation of integrin β2 as a CAR T cellular therapy target

Safely expanding indications for cellular therapies has been challenging given a lack of highly cancer-specific surface markers. Here we explore the hypothesis that tumor cells express cancer-specific surface protein conformations that are invisible to standard target discovery pipelines evaluating gene or protein expression, and these conformations can be identified and immunotherapeutically targeted. We term this strategy integrating cross-linking mass spectrometry with glycoprotein surface capture 'structural surfaceomics'. As a proof of principle, we apply this technology to acute myeloid leukemia (AML), a hematologic malignancy with dismal outcomes and no known optimal immunotherapy target. We identify the activated conformation of integrin beta(2) as a structurally defined, widely expressed AML-specific target. We develop and characterize recombinant antibodies to this protein conformation and show that chimeric antigen receptor T cells eliminate AML cells and patient-derived xenografts without notable toxicity toward normal hematopoietic cells. Our findings validate an AML conformation-specific target antigen and demonstrate a tool kit for applying these strategies more broadly.

Automated summary

This study explores a new strategy called structural surfaceomics for identifying and targeting cancer-specific surface protein conformations on tumor cells. The researchers successfully applied this technology to acute myeloid leukemia (AML) and identified an AML-specific target. They developed antibodies to this protein conformation and demonstrated that chimeric antigen receptor T cells can eliminate AML cells without toxicity to normal cells.