Division of Pathology, Singapore General Hospital, Singapore, Singapore.
Singapore Immunology Network (SIgN), Agency of Science, Technology and Research (ASTAR), Singapore, Singapore.
Front Immunol. 2018 May 30;9:1209. doi: 10.3389/fimmu.2018.01209. eCollection 2018.
Breast cancer is the most common malignancy affecting women, but the heterogeneity of the condition is a significant obstacle to effective treatment. Triple negative breast cancers (TNBCs) do not express HER2 or the receptors for estrogen or progesterone, and so often have a poor prognosis. Tumor-infiltrating T cells have been well-characterized in TNBC, and increased numbers are associated with better outcomes; however, the potential roles of B cells and plasma cells have been large. Here, we conducted a retrospective correlative study on the expression of B cell/plasma cell-related genes, and the abundance and localization of B cells and plasma cells within TNBCs, and clinical outcome. We analyzed 269 TNBC samples and used immunohistochemistry to quantify tumor-infiltrating B cells and plasma cells, coupled with NanoString measurement of expression of immunoglobulin metagenes. Multivariate analysis revealed that patients bearing TNBCs with above-median densities of CD38 plasma cells had significantly better disease-free survival (DFS) (HR = 0.44; 95% CI 0.26-0.77; = 0.004) but not overall survival (OS), after adjusting for the effects of known prognostic factors. In contrast, TNBCs with higher immunoglobulin gene expression exhibited improved prognosis (OS = 0.029 and DFS = 0.005). The presence of B cells and plasma cells was positively correlated ( < 0.0001, = 0.558), while immunoglobulin gene IGKC, IGHM, and IGHG1 mRNA expression correlated specifically with the density of CD38 plasma cells (IGKC < 0.0001, = 0.647; IGHM < 0.0001, = 0.580; IGHG1 < 0.0001, = 0.655). Interestingly, after adjusting the multivariate analysis for the effect of intratumoral CD38 plasma cell density, the expression levels of all three genes lost significant prognostic value, suggesting a biologically important role of plasma cells. Last but not least, the addition of intratumoral CD38 plasma cell density to clinicopathological features significantly increased the prognostic value for both DFS (ΔLRχ = 17.28, = 1.71E-08) and OS (ΔLRχ = 10.03, = 6.32E-08), compared to clinicopathological features alone. The best combination was achieved by integrating intratumoral CD38 plasma cell density and IGHG1 which conferred the best added prognostic value for DFS (ΔLRχ = 27.38, = 5.22E-10) and OS (ΔLRχ = 21.29, = 1.03E-08). Our results demonstrate that the role of plasma cells in TNBC warrants further study to elucidate the relationship between their infiltration of tumors and disease recurrence.
乳腺癌是最常见的影响女性的恶性肿瘤，但该疾病的异质性是有效治疗的重大障碍。三阴性乳腺癌（TNBC）不表达 HER2 或雌激素或孕激素受体，因此预后通常较差。TNBC 中已经很好地描述了肿瘤浸润性 T 细胞，并且数量增加与更好的结果相关；然而，B 细胞和浆细胞的潜在作用仍然很大。在这里，我们对 B 细胞/浆细胞相关基因的表达、TNBC 中 B 细胞和浆细胞的丰度和定位以及临床结果进行了回顾性相关研究。我们分析了 269 例 TNBC 样本，并使用免疫组织化学方法定量测定肿瘤浸润性 B 细胞和浆细胞，同时结合 NanoString 测量免疫球蛋白基因荟萃分析。多变量分析显示，在调整已知预后因素的影响后，具有高于中位数的 CD38 浆细胞密度的 TNBC 患者的无病生存率（DFS）（HR=0.44；95%CI 0.26-0.77；=0.004）显著改善，但总生存率（OS）没有改善。相比之下，具有更高免疫球蛋白基因表达的 TNBC 患者的预后得到改善（OS=0.029 和 DFS=0.005）。B 细胞和浆细胞的存在呈正相关（<0.0001，=0.558），而免疫球蛋白基因 IGKC、IGHM 和 IGHG1 mRNA 表达与 CD38 浆细胞的密度呈特异性相关（IGKC<0.0001，=0.647；IGHM<0.0001，=0.580；IGHG1<0.0001，=0.655）。有趣的是，在调整多变量分析中肿瘤内 CD38 浆细胞密度的影响后，所有三个基因的表达水平均失去了显著的预后价值，表明浆细胞具有重要的生物学作用。最后但同样重要的是，将肿瘤内 CD38 浆细胞密度与临床病理特征相结合，与仅临床病理特征相比，显著提高了 DFS（ΔLRχ=17.28，=1.71E-08）和 OS（ΔLRχ=10.03，=6.32E-08）的预后价值。最佳组合是通过整合肿瘤内 CD38 浆细胞密度和 IGHG1 来实现的，这为 DFS（ΔLRχ=27.38，=5.22E-10）和 OS（ΔLRχ=21.29，=1.03E-08）提供了最佳的附加预后价值。我们的研究结果表明，浆细胞在 TNBC 中的作用值得进一步研究，以阐明其浸润肿瘤与疾病复发之间的关系。
