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B-ALL GPR65 expression influences susceptibility to CAR-T therapy through a VEGF and macrophage-dependent mechanism [bulk RNA-Seq]

ABSTRACT: Chimeric antigen receptor (CAR)-T cell therapy has shown promise in treating CD19+ hematological tumors, but some patients fail to respond. Here we used an immune-competent mouse model of B cell acute lymphoblastic leukemia (B-ALL) to assess clonal tumor populations with distinct responses to CAR-T cell therapy. We identified GPR65 as a determinant of tumor responsiveness to CAR-T cell therapy, with high GPR65 expression associated with a complete response. GPR65 KO tumors were resistant to CAR-T treatment in vivo. This was associated with increased tumor VEGFA expression driven by FOXO1 activation and expanded host macrophages. Either depletion of host macrophages or deletion of VEGFA from GPR65 KO tumors restored responsiveness to CAR-T cell treatment. Anti-VEGFa therapy, in combination with CD19-CAR-T, prolongs the survival of GPR65-KO tumor-bearing mice in pre-clinical models. Our results indicate that GPR65 may be a useful biomarker for tumor responsiveness to CAR-T cell therapy and further suggest VEGFA or host macrophages as therapeutic targets to improve CAR-T efficacy.

ORGANISM(S): Mus musculus

PROVIDER: GSE266164 | GEO | 2025/01/30

REPOSITORIES: GEO

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B-ALL GPR65 expression influences susceptibility to CAR-T therapy through a VEGF and macrophage-dependent mechanism [bulk RNA-Seq]

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