RHOA 功能缺失损害 IFN-γ 应答并促进 CD19 抗原逃逸驱动弥漫大 B 细胞淋巴瘤 CAR-T 耐药

CD19-directed chimeric antigen receptor (CAR)-T cells are breakthrough therapies for aggressive B-cell lymphomas, but less than half of patients achieve durable responses.

We previously showed through whole-genome sequencing of tumors from CAR-T-treated patients that deletions of RHOA (3p21. 31) are enriched in cases progressing after treatment. RHOA 's roles in resistance and pathogenesis are poorly defined, despite loss-of-function alterations that occur in ~20% of newly diagnosed diffuse large B-cell lymphoma (DLBCL) cases.

To evaluate mechanisms of CAR-T resistance, we created RHOA-deficient DLBCL systems and confirmed cell-intrinsic loss of response to CAR-19 in vitro and in vivo. RHOA loss promotes AKT activation that impairs cell-intrinsic responses to interferon gamma (IFN ).

Moreover, expression of the CAR target CD19 is consistently down-regulated accompanied by a drive toward plasmablast differentiation. RHOA deficient tumors demonstrate greatly increased sensitivity to AKT-pathway inhibitors, which reverse impaired IFN responses. Lymphoma microenvironments in vivo in immunocompetent mice reveal that RHOA loss promotes decreased infiltration by cytotoxic T cells and enrichment of M2-polarized macrophages, known markers of CAR-T resistance in lymphoma clinical cases.

Overall, we characterize RHOA deficiency as an AKT-mediated CAR-T resistance driver and implicate avoidance of T-cell mediated killing as a likely reason for RHOA's frequent loss in DLBCL pathogenesis.