Background/Objectives: In recent years, efforts by the scientific community to elucidate the underlying mechanisms of clonal expansion and selection within tumors have led to the theory of “tumor ecosystems”, implicating, among other factors, the role of the microenvironment in therapy resistance and tumor progression. In this context, the contribution of the microenvironment in the development of multiple myeloma (MM) is being investigated, imparting great emphasis on continuous clonal evolution. This process gives rise to aggressive clones with the potential to spread to extramedullary sites, rendering any treatment strategy practically ineffective. This systematic review aimed to gather knowledge about the immune microenvironment (IME) of extramedullary plasma cell myeloma and the differences in immune synthesis between medullary and extramedullary disease (EMD). Methods: A search strategy according to PRISMA guidelines was conducted in seven databases, and six articles meeting the inclusion criteria were encompassed in the study. Results: Results obtained from molecular analysis as well as flow cytometry and immunofluorescence indicated profound genetic instability at EMD sites along with spatial and temporal heterogeneity of the IME, implying a possible correlation between them. Both genetic and microenvironment variability were notably greater in EMD compared to medullary disease. The establishment of an immunosuppressive microenvironment was the rule, with exhausted CD8+ and natural killer (NK) cells, M2 macrophages, and inactivated dendritic cells found co-localized with neoplastic plasma cells, whereas cytotoxic CD8+ cells, M1 macrophages, and active dendritic cells congregated in tumor-free areas. Post-therapy alterations in the immune milieu were also noted and were concerned mostly the percentages of Tregs and MDSCs. Conclusions: The recognition of the microenvironment-myeloma cell interplay is essential for designing specific therapeutic strategies and ameliorating disease prognosis.
背景/目的：近年来，科学界为阐明肿瘤内部克隆扩增与选择的内在机制，提出了"肿瘤生态系统"理论，指出微环境在治疗抵抗和肿瘤进展中具有重要作用。在此背景下，多发性骨髓瘤（MM）发展过程中微环境的作用正受到关注，研究重点聚焦于持续克隆演化过程。该过程会产生具有髓外扩散潜能的侵袭性克隆，导致现有治疗策略基本失效。本系统综述旨在整合关于髓外浆细胞瘤免疫微环境（IME）的知识，以及髓内与髓外病变（EMD）在免疫构成方面的差异。方法：按照PRISMA指南在七个数据库中实施检索策略，最终纳入六篇符合标准的文献。结果：分子分析、流式细胞术及免疫荧光结果显示，EMD部位存在显著的遗传不稳定性，且IME呈现时空异质性，提示两者可能存在关联。与髓内病变相比，EMD的遗传变异和微环境异质性均更为显著。免疫抑制微环境的形成呈现规律性特征：耗竭型CD8+细胞、自然杀伤（NK）细胞、M2型巨噬细胞及失活树突状细胞与肿瘤性浆细胞共定位，而细胞毒性CD8+细胞、M1型巨噬细胞及活化树突状细胞则聚集于无瘤区域。研究还观察到治疗后免疫环境的变化，主要体现在调节性T细胞（Tregs）和髓源性抑制细胞（MDSCs）的比例改变。结论：认识微环境与骨髓瘤细胞的相互作用机制，对制定特异性治疗策略及改善疾病预后具有重要意义。
Unveiling Extramedullary Myeloma Immune Microenvironment: A Systematic Review
肿瘤(癌症)患者之家