Boulogeorgou Kassiani, Papaioannou Maria, Chatzileontiadou Sofia, Georgiou Elisavet, Fola Amalia, Tzorakoleftheraki Sofia-Eleni, Hatjiharissi Evdoxia, Koletsa Triantafyllia
Department of Pathology, School of Medicine, Aristotle University of Thessaloniki, University Campus, 54124 Thessaloniki, Greece.
Hematology Unit, 1st Department of Internal Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece.
Cancers (Basel). 2025 Mar 24;17(7):1081. doi: 10.3390/cancers17071081.
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).
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 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.
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克隆扩增和选择的潜在机制所做的努力催生了“肿瘤生态系统”理论，该理论认为，除其他因素外，微环境在治疗耐药性和肿瘤进展中发挥着作用。在此背景下，人们正在研究微环境在多发性骨髓瘤（MM）发展中的作用，特别强调克隆的持续进化。这一过程会产生具有扩散至髓外部位潜力的侵袭性克隆，使任何治疗策略实际上都无效。本系统综述旨在收集有关髓外浆细胞骨髓瘤免疫微环境（IME）以及髓内和髓外疾病（EMD）免疫合成差异的知识。
根据PRISMA指南在七个数据库中进行检索策略，该研究纳入了六篇符合纳入标准的文章。
分子分析以及流式细胞术和免疫荧光获得的结果表明，EMD部位存在严重的基因不稳定以及IME的时空异质性，这意味着它们之间可能存在相关性。与髓内疾病相比，EMD中的基因和微环境变异性明显更大。免疫抑制微环境的形成是常态，耗尽的CD8 +和自然杀伤（NK）细胞、M2巨噬细胞以及失活的树突状细胞与肿瘤性浆细胞共定位，而细胞毒性CD8 +细胞、M1巨噬细胞和活性树突状细胞聚集在无肿瘤区域。还注意到治疗后免疫环境的变化，主要涉及调节性T细胞（Tregs）和骨髓来源的抑制性细胞（MDSCs）的百分比。
认识微环境与骨髓瘤细胞之间的相互作用对于设计特定的治疗策略和改善疾病预后至关重要。
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