Language

English

Publication Date

11-1-2023

Journal

Nature Cancer

DOI

10.1038/s43018-023-00652-6

PMID

37904046

PMCID

PMC10663162

PubMedCentral® Posted Date

10-30-2023

PubMedCentral® Full Text Version

Post-print

Abstract

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 β2 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.

Keywords

Humans, Receptors, Chimeric Antigen, T-Lymphocytes, Integrins, Immunotherapy, Adoptive, Leukemia, Myeloid, Acute, Cancer immunotherapy, Acute myeloid leukaemia, Proteomics, Cancer

Published Open-Access

yes

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