肿瘤细胞治疗研究
英文原题：Identification of potential resistance mechanisms and therapeutic targets for the relapse of BCMA CAR-T therapy in relapsed/refractory multiple myeloma through single-cell sequencing.
Identification of potential resistance mechanisms and therapeutic targets for the relapse of BCMA CAR-T therapy in relapsed/refractory multiple myeloma through single-cell sequencing.
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我们比较了 BCMA CAR-T 治疗前和 BCMA CAR-T 治疗后复发时 CD45 + BM 细胞的异质性。
BCMA CAR-T 治疗复发/难治性多发性骨髓瘤（R/R-MM）疗效很高，可显著改善患者生存。然而，治疗后的缓解时间较短、复发率较高，仍是限制长期生存的瓶颈，这可能与 R/R-MM 骨髓（BM）免疫微环境有关。本研究旨在通过单细胞 RNA 测序（scRNA-seq）分析 BM 浆细胞和免疫细胞，深入解析耐药机制并探索 BCMA CAR-T 治疗后复发的潜在新靶点。
研究采用 10X Genomics scRNA-seq，鉴定 BCMA CAR-T 治疗前及治疗后复发时 R/R-MM CD45⁺ BM 细胞群。使用 Cell Ranger 流程和 CellChat 进行详细分析。
比较 CAR-T 治疗前与复发时 CD45⁺ BM 细胞异质性后，我们发现复发时单核细胞/巨噬细胞比例增加，而 T 细胞比例下降。随后对治疗前和复发时 BM 微环境中的浆细胞、T 细胞、NK 细胞、DC、中性粒细胞及单核细胞/巨噬细胞重新聚类并分析变化。复发时 BCMA 阳性浆细胞比例增加。复发患者浆细胞还表达其他靶点，包括 CD38、CD24、SLAMF7、CD138 和 GPRC5D。此外，BCMA CAR-T 治疗后复发的 R/R-MM 患者中，耗竭 T 细胞、TIGIT⁺ NK 细胞、干扰素应答型 DC 和干扰素应答型中性粒细胞均增加。IL1 高表达巨噬细胞、S100A9 高表达巨噬细胞、干扰素应答型巨噬细胞、CD16 高表达巨噬细胞、MARCO 高表达巨噬细胞和 S100A11 高表达巨噬细胞比例显著增加。细胞间通讯分析显示，单核细胞/巨噬细胞，尤其是 MIF 和 APRIL 信号通路，是 CAR-T 治疗后 R/R-MM 复发的关键因素。
我们的数据拓展了对 R/R-MM 患者 BCMA CAR-T 治疗内源性和外源性复发的认识，揭示抗原改变和诱导免疫抑制微环境的潜在机制，可为优化 BCMA CAR-T 策略提供依据。仍需进一步研究确认这些发现。
BCMA CAR-T is highly effective for relapsed/refractory multiple myeloma(R/R-MM) and significantly improves the survival of patients. However, the short remission time and high relapse rate of MM patients treated with BCMA CAR-T remain bottlenecks that limit long-term survival. The immune microenvironment of the bone marrow (BM) in R/R-MM may be responsible for this. The present study aims to present an in-depth analysis of resistant mechanisms and to explore potential novel therapeutic targets for relapse of BCMA CAR-T treatment via single-cell RNA sequencing (scRNA-seq) of BM plasma cells and immune cells.
This study used 10X Genomic scRNA-seq to identify cell populations in R/R-MM CD45 + BM cells before BCMA CAR-T treatment and relapse after BCMA CAR-T treatment. Cell Ranger pipeline and CellChat were used to perform detailed analysis.
We compared the heterogeneity of CD45 + BM cells before BCMA CAR-T treatment and relapse after BCMA CAR-T treatment. We found that the proportion of monocytes/macrophages increased, while the percentage of T cells decreased at relapse after BCMA CAR-T treatment. We then reclustered and analyzed the alterations in plasma cells, T cells, NK cells, DCs, neutrophils, and monocytes/macrophages in the BM microenvironment before BCMA CAR-T treatment and relapse after BCMA CAR-T treatment. We show here that the percentage of BCMA positive plasma cells increased at relapse after BCMA CAR-T cell therapy. Other targets such as CD38, CD24, SLAMF7, CD138, and GPRC5D were also found to be expressed in plasma cells of the R/R-MM patient at relapse after BCMA CAR-T cell therapy. Furthermore, exhausted T cells, TIGIT + NK cells, interferon-responsive DCs, and interferon-responsive neutrophils, increased in the R/R-MM patient at relapse after BCMA CAR-T cell treatment. Significantly, the proportion of IL1 hi M , S100A9 hi M , interferon-responsive M , CD16 hi M , MARCO hi M , and S100A11 hi M significantly increased in the R/R-MM patient at relapse after BCMA CAR-T cell therapy. Cell-cell communication analysis indicated that monocytes/macrophages, especially the MIF and APRIL signaling pathway are key players in R/R-MM patient at relapse after BCMA CAR-T cell therapy.
Taken together, our data extend the understanding of intrinsic and extrinsic relapse of BCMA CAR-T treatment in R/R-MM patient and the potential mechanisms involved in the alterations of antigens and the induced immunosuppressive microenvironment, which may provide a basis for the optimization of BCMA CAR-T strategies. Further studies should be performed to confirm these findings.
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