肿瘤细胞治疗研究
英文原题：Immune checkpoint remodeling across disease progression in multiple myeloma.
Immune checkpoint remodeling across disease progression in multiple myeloma.
骨髓（BM）内的免疫检查点动态在很大程度上决定了多发性骨髓瘤（MM）的疾病演变和治疗反应。
骨髓（BM）中的免疫检查点动态变化对多发性骨髓瘤（MM）的疾病演变和治疗反应具有关键影响。为描绘浆细胞恶性肿瘤演变过程中BM内的免疫重塑，我们对健康供者（HD，n=25）、意义未明的单克隆丙种球蛋白病（MGUS，n=17）、新诊断MM（NDMM，n=57）和复发/复发难治性MM（MM，n=72；治疗中n=27，治疗间歇n=12）的适应性免疫及部分固有免疫区室中的抑制性检查点（PD-1、CTLA-4、LAG-3、TIM-3、TIGIT、BTLA和2B4）及共刺激检查点（ICOS、CD27、DNAM-1、4-1BB和OX40）进行了分析。疾病进展的特征是成熟、记忆和活化/增殖B细胞亚群的丢失，以及NDMM特异性的浆母细胞/浆细胞扩增。B细胞成熟伴随抑制性受体的广泛重塑（尤其是成熟B细胞上PD-1、TIM-3、TIGIT和2B4降低；活化B细胞和浆母细胞/浆细胞上CTLA-4减少；浆母细胞/浆细胞上TIM-3、LAG-3和2B4降低），同时伴有选择性共刺激变化（成熟B细胞上OX40降低；活化和浆母细胞/浆细胞区室CD27丢失；4-1BB调控呈差异性）。T细胞区室表现为早期CD4+扩增伴CD8+细胞毒性减少及检查点变化：PD-1广泛下调，同时LAG-3、TIM-3、TIGIT和BTLA在特定亚群中升高；CD27、DNAM-1和ICOS上调程度不一；4-1BB持续丢失。NKT和γδ T细胞频率稳定，但其检查点发生重构：NKT细胞表现为PD-1和4-1BB降低、TIGIT、LAG-3和DNAM-1升高，而γδ T细胞则表现为CTLA-4、BTLA和共刺激受体OX40减少。固有NK细胞表现出频率降低和表型改变，包括TIM-3和PD-1降低、4-1BB和OX40缺失、TIGIT和2B4呈阶段特异性升高以及DNAM-1升高。检查点改变，如低TIGIT或CTLA-4以及OX40表达升高，与更优的无进展生存期相关。MM进展涉及BM中抑制性和激活性免疫检查点的广泛、阶段和亚群特异性重塑，这对免疫治疗靶向具有重要意义。
Immune checkpoint dynamics within the bone marrow (BM) critically shape disease evolution and therapeutic responses in multiple myeloma (MM). To delineate immune remodeling in the BM during plasma cell malignancy evolution, we profiled inhibitory (PD-1, CTLA-4, LAG-3, TIM-3, TIGIT, BTLA, and 2B4) and co-stimulatory (ICOS, CD27, DNAM-1, 4-1BB, and OX40) checkpoints across adaptive and select innate compartments in healthy donors (HD, n=25), monoclonal gammopathy of undetermined significance (MGUS, n=17), newly diagnosed MM (NDMM, n=57), and relapsed/relapsed-refractory MM (MM, n=72; on-treatment n=27, off-treatment n=12). Progressive disease featured loss of mature, memory, and activated/proliferating B cell subsets and an NDMM-specific expansion of plasmablasts/plasma cells. B cell maturation was accompanied by broad remodeling of inhibitory receptors (notably reduced PD-1, TIM-3, TIGIT, and 2B4 on mature B cells; decreased CTLA-4 on activated B cells and plasmablasts/plasma cells; and reduced TIM-3, LAG-3, and 2B4 on plasmablasts/plasma cells) alongside selective co-stimulatory changes (OX40 decreased on mature B cells; CD27 loss on activated and plasmablast/plasma compartments; divergent 4-1BB regulation). T cell compartments showed early CD4+ expansion with CD8+ cytotoxic reduction and checkpoint shifts: broad PD-1 downregulation with subset-restricted increases in LAG-3, TIM-3, TIGIT, and BTLA; variable upregulation of CD27, DNAM-1, and ICOS; and consistent 4-1BB loss. NKT and γδ T cell frequencies were stable, but their checkpoints were reconfigured: NKT cells exhibited decreased PD-1 and 4-1BB and increased TIGIT, LAG-3, and DNAM-1, whereas γδ T cells showed reduced CTLA-4, BTLA, and the co-stimulatory receptor OX40. Innate NK cells demonstrated reduced frequency and phenotypic shifts, including decreased TIM-3 and PD-1, loss of 4-1BB and OX40, stage-specific increases in TIGIT and 2B4, and elevated DNAM-1. Checkpoint alterations, such as low TIGIT or CTLA-4 and elevated OX40 expression, were correlated with superior progression-free survival. MM progression entails extensive, stage- and subset-specific remodeling of inhibitory and activating immune checkpoints in the BM, with implications for immunotherapeutic targeting.
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