Bristol Myers Squibb, Seattle, Washington, United States of America.
Sage Bionetworks, Seattle, Washington, United States of America.
PLoS Med. 2020 Nov 4;17(11):e1003323. doi: 10.1371/journal.pmed.1003323. eCollection 2020 Nov.
The tumor microenvironment (TME) is increasingly appreciated as an important determinant of cancer outcome, including in multiple myeloma (MM). However, most myeloma microenvironment studies have been based on bone marrow (BM) aspirates, which often do not fully reflect the cellular content of BM tissue itself. To address this limitation in myeloma research, we systematically characterized the whole bone marrow (WBM) microenvironment during premalignant, baseline, on treatment, and post-treatment phases.
Between 2004 and 2019, 998 BM samples were taken from 436 patients with newly diagnosed MM (NDMM) at the University of Arkansas for Medical Sciences in Little Rock, Arkansas, United States of America. These patients were 61% male and 39% female, 89% White, 8% Black, and 3% other/refused, with a mean age of 58 years. Using WBM and matched cluster of differentiation (CD)138-selected tumor gene expression to control for tumor burden, we identified a subgroup of patients with an adverse TME associated with 17 fewer months of progression-free survival (PFS) (95% confidence interval [CI] 5-29, 49-69 versus 70-82 months, χ2 p = 0.001) and 15 fewer months of overall survival (OS; 95% CI -1 to 31, 92-120 versus 113-129 months, χ2 p = 0.036). Using immunohistochemistry-validated computational tools that identify distinct cell types from bulk gene expression, we showed that the adverse outcome was correlated with elevated CD8+ T cell and reduced granulocytic cell proportions. This microenvironment develops during the progression of premalignant to malignant disease and becomes less prevalent after therapy, in which it is associated with improved outcomes. In patients with quantified International Staging System (ISS) stage and 70-gene Prognostic Risk Score (GEP-70) scores, taking the microenvironment into consideration would have identified an additional 40 out of 290 patients (14%, premutation p = 0.001) with significantly worse outcomes (PFS, 95% CI 6-36, 49-73 versus 74-90 months) who were not identified by existing clinical (ISS stage III) and tumor (GEP-70) criteria as high risk. The main limitations of this study are that it relies on computationally identified cell types and that patients were treated with thalidomide rather than current therapies.
In this study, we observe that granulocyte signatures in the MM TME contribute to a more accurate prognosis. This implies that future researchers and clinicians treating patients should quantify TME components, in particular monocytes and granulocytes, which are often ignored in microenvironment studies.
肿瘤微环境（TME）越来越被认为是癌症预后的重要决定因素，包括多发性骨髓瘤（MM）。然而，大多数骨髓瘤微环境研究都是基于骨髓（BM）抽吸物，这些研究通常不能完全反映 BM 组织本身的细胞含量。为了解决骨髓瘤研究中的这一局限性，我们系统地描述了在前期、基线、治疗中和治疗后阶段整个骨髓（WBM）的微环境。
2004 年至 2019 年，在美国阿肯色大学医学科学小石城分校共采集了 436 例新诊断多发性骨髓瘤（NDMM）患者的 998 份 BM 样本。这些患者中 61%为男性，39%为女性，89%为白人，8%为黑人，3%为其他/拒绝，平均年龄为 58 岁。通过 WBM 和匹配的 CD138 选择的肿瘤基因表达来控制肿瘤负担，我们确定了一组与无进展生存期（PFS）减少 17 个月（95%置信区间 [CI] 5-29，49-69 与 70-82 个月，χ2 p = 0.001）和总生存期（OS）减少 15 个月相关的不良 TME 的患者（95%CI -1 至 31，92-120 与 113-129 个月，χ2 p = 0.036）。使用免疫组织化学验证的计算工具，从批量基因表达中识别不同的细胞类型，我们表明不良结果与 CD8+T 细胞升高和粒细胞比例降低有关。这种微环境在前期向恶性疾病的进展过程中发展，并在治疗后变得不那么普遍，在治疗后与改善的结果相关。在具有量化国际分期系统（ISS）分期和 70 基因预后风险评分（GEP-70）评分的患者中，考虑微环境可以在不通过现有临床（ISS 分期 III）和肿瘤（GEP-70）标准识别为高危的情况下，额外识别出 290 名患者中的 40 名（14%，前突变 p = 0.001），他们的预后（PFS，95%CI 6-36，49-73 与 74-90 个月）明显更差。本研究的主要局限性是它依赖于计算识别的细胞类型，并且患者接受了沙利度胺治疗，而不是目前的治疗方法。
在这项研究中，我们观察到 MM TME 中的粒细胞特征有助于更准确地预测预后。这意味着未来的研究人员和治疗患者的临床医生应该量化 TME 成分，特别是在微环境研究中经常被忽视的单核细胞和粒细胞。
