R-ISS Stage-Dependent Single-Cell Sequencing Analysis Uncovers Oncogenes and Potential Immunotherapeutic Targets in Multiple Myeloma

Multiple myeloma (MM) accounts for ~10% of all haematologic malignancies. Little is known about high intratumour heterogeneities in patients stratified by the Revised International Staging System (R-ISS). Herein, we constructed a single-cell transcriptome atlas to compare differential expression patterns among stages. We found that a novel cytotoxic plasma cell (PC) population exhibited with NKG7 positive was obviously enriched in stage II patients. Additionally, a malignant plasma cell population with significantly elevated expression of MKI67 and PCNA was associated with unfavourable prognosis and Epstein-Barr virus (EBV) infection in our collected samples. Moreover, Ribonucleotide Reductase Regulatory Subunit M2 (RRM2) was found and verified to promote proliferation of MM cell lines, suggesting RRM2 may serve as a detrimental marker in MM. The percentages of CD8+ T cells and NKT cells decreased along with R-ISS stages, reflecting the plasticity of the tumour immune microenvironment. Importantly, their crosstalks with myeloid cells and PC identified several potential immunotargets such as SIRPA-CD47, and CD74-MIF, respectively. Collectively, this study provided an R-ISS-related single-cell MM atlas and revealed the clinical significance of novel PC clusters, as well as potential immunotargets in MM progression.

多发性骨髓瘤（MM）约占所有血液系统恶性肿瘤的10%。对于根据修订的国际分期系统（R - ISS）进行分层的患者体内的高度肿瘤内异质性，人们知之甚少。在此，我们构建了一个单细胞转录组图谱来比较各分期之间的差异表达模式。我们发现一种新型的NKG7阳性细胞毒性浆细胞（PC）群在II期患者中明显富集。此外，在我们收集的样本中，一种MKI67和PCNA表达显著升高的恶性浆细胞群与不良预后以及爱泼斯坦 - 巴尔病毒（EBV）感染有关。而且，核糖核苷酸还原酶调节亚基M2（RRM2）被发现并经证实可促进MM细胞系的增殖，这表明RRM2可能作为MM中的一个不良标志物。CD8 + T细胞和NKT细胞的百分比随着R - ISS分期而降低，反映了肿瘤免疫微环境的可塑性。重要的是，它们与髓系细胞和浆细胞的相互作用分别确定了几个潜在的免疫靶点，如SIRPA - CD47和CD74 - MIF。总之，这项研究提供了一个与R - ISS相关的单细胞MM图谱，并揭示了新型浆细胞群的临床意义以及MM进展中的潜在免疫靶点。