粒细胞性髓源性抑制细胞在 CAR-T 治疗中的功能作用：来自多发性骨髓瘤单细胞 RNA 测序的见解

Immunotherapies, including chimeric antigen receptor T-cell (CAR-T) therapy, represent a pivotal approach in the treatment of multiple myeloma (MM). However, the complex immunosuppressive tumor microenvironment (TME) poses significant challenges to their efficacy. Among the immunosuppressive cells in the MM TME, granulocytic myeloid-derived suppressor cells (G-MDSCs) are predominant, yet their functions remain incompletely understood. This study aimed to comprehensively analyze the role of G-MDSCs in MM patients undergoing CAR-T therapy.

Single-cell transcriptomic data from seven MM patients before and after CAR-T therapy were analyzed to characterize G-MDSCs. Functional enrichment and gene set enrichment analysis (GSEA) were performed to identify signaling pathways. A risk prediction model was constructed using RNA-seq and survival data from 713 MM patients, and validated by Kaplan-Meier analysis. In vitro experiments were conducted to assess the immunosuppressive functions of G-MDSCs.

The findings, though exploratory due to limited sample size and inter-patient heterogeneity, suggested pathological activation and immunosuppressive roles of G-MDSCs potentially linked to patient prognosis. G-MDSCs were identified as key modulators of immune responses within the TME, with GSEA indicating regulation via IFN- / signaling. They may facilitate immune evasion of MM cells by promoting proliferation through the IGF1-IGF1R axis and inhibiting T cells and other immune cells via the SIRPA-CD47 pathway. The risk prediction model based on G-MDSC gene signatures demonstrated high prognostic accuracy (AUC = 0.94). PTGS1 was identified as a key marker associated with high-risk groups, and functional assays confirmed its role in mediating G-MDSC immunosuppressive activity.

This study provides preliminary insights into the functional role of G-MDSCs in the MM TME and highlights their impact on CAR-T therapy outcomes. The findings suggest potential therapeutic strategies, including targeting PTGS1, to enhance CAR-T efficacy. Larger and more diverse cohorts are required to substantiate these observations.