Department of Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133, Milan, Italy.
Hematology Department, Institut Catala d'Oncologia-Hospitalet, Barcelona, Spain.
Ann Hematol. 2019 Jul;98(7):1713-1720. doi: 10.1007/s00277-019-03648-4. Epub 2019 May 3.
Symptomatic multiple myeloma (MM) is a plasma cell neoplasm that represents the final stage of a continuum of clinical conditions that start from monoclonal gammopathy of unknown significance (MGUS), then transits in the more advance, but still asymptomatic, smoldering MM (SMM), with a final evolution in symptomatic MM. To investigate SMM microenvironment modifications, we studied 16 patients diagnosed at our hospital. Eight of them (group A) developed MM within 2 years from diagnosis while the others (group B) had stable SMM. Samples were bone marrow biopsies at diagnosis and after 2 years (± 4 months) and were analyzed by immunohistochemical analysis. Firstly, we found a significant increase in both CD4+ cells (11 vs 17%, p < 0.01) and CD8+ cells (15 vs 18%, p < 0.01) between diagnosis and at follow-up samples (whole cohort). This was associated to an increase in the CD4+/CD8+ ratio (0.74 vs 0.93, p < 0.01). Secondly, we discovered an increased expression of T cell inhibitory molecules during SMM evolution. In fact, plasma cell PD-L1 and microenvironment cell LAG3 expression increased from 1 to 12% (p = 0.03) and 4 to 10% (p = 0.04), respectively, from diagnosis to follow-up. Also, plasma cells and microenvironment cells HLA-DR expression augmented during SMM evolution from 7 to 10% (p = 0.04) and 29 to 39% (p = 0.01), respectively. When comparing group A vs group B, we found an increased CD68-KP1+ cell infiltration in favor of group B at diagnosis (23 vs 28%, p = 0.01) and a greater plasma cell infiltration at follow-up (50 vs 26%, p < 0.01). Our findings suggest how immune escape mechanisms appear earlier during multiple myeloma evolution, and that LAG3 could be a possible immunologic target in this setting.
有症状多发性骨髓瘤（MM）是一种浆细胞肿瘤，代表了从意义未明的单克隆丙种球蛋白血症（MGUS）开始的一系列临床病症的终末阶段，然后过渡到更高级但仍无症状的冒烟型 MM（SMM），最终发展为有症状 MM。为了研究 SMM 微环境的改变，我们研究了在我院诊断的 16 名患者。其中 8 名（A 组）在诊断后 2 年内发展为 MM，而其他 8 名（B 组）则为稳定的 SMM。在诊断时和 2 年后（±4 个月）采集骨髓活检样本，并通过免疫组织化学分析进行分析。首先，我们发现整个队列中，与诊断时相比，CD4+细胞（11%对 17%，p<0.01）和 CD8+细胞（15%对 18%，p<0.01）均显著增加。这与 CD4+/CD8+比值（0.74 对 0.93，p<0.01）的增加有关。其次，我们发现 SMM 进展过程中 T 细胞抑制分子的表达增加。事实上，从诊断到随访，浆细胞 PD-L1 和微环境细胞 LAG3 的表达分别从 1%增加到 12%（p=0.03）和从 4%增加到 10%（p=0.04）。此外，SMM 进展过程中浆细胞和微环境细胞 HLA-DR 的表达也增加，从 7%增加到 10%（p=0.04）和从 29%增加到 39%（p=0.01）。比较 A 组和 B 组时，我们发现 A 组在诊断时的 CD68-KP1+细胞浸润更为明显（23%对 28%，p=0.01），而 B 组在随访时的浆细胞浸润更为明显（50%对 26%，p<0.01）。我们的研究结果表明，免疫逃逸机制在多发性骨髓瘤的进展过程中出现得更早，并且 LAG3 可能是这种情况下的一个潜在免疫治疗靶点。
