Cai Chen, Zhang Jin, Li Minyu, Wu Zhen-Jie, Song Ken H, Zhan Tina W, Wang Lin-Hui, Sun Ying-Hao
Department of Special Clinic, Changzheng Hospital, Second Military Medical University, Shanghai, 200433, China.
Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
Tumour Biol. 2016 Jun;37(6):8209-18. doi: 10.1007/s13277-015-4687-1. Epub 2015 Dec 30.
Renal cell carcinoma is among the leading causes of cancer-related death and was found to induce IL-10. We started by focusing on IL-10-secreting cells in tumor-infiltrating lymphocytes in renal cell carcinoma patients and observed that both CD3(+) T cells and CD19(+) B cells contributed to an elevated IL-10 expression. We then focused on IL-10-expressing B cells, and found that compared to non-IL-10-producing B cells, the IL-10-expressing B cells had significantly lower levels of CD19 and CD20 expression, a lack of IgM and IgD expression, while the level of CD27 was elevated. Moreover, culturing under unstimulated conditions resulted in higher antibody production by these IL-10-producing B cells than their peripheral blood counterparts, which strongly suggested that they are plasmablast-differentiating cells. Both IgA and IgG subtypes were found but IgA had a higher relative abundance in the tumor-infiltrating fraction. We then observed inverse correlations between the frequency of IL-10-producing B cells and pro-inflammatory cytokine-producing T cells and T cell proliferation. The expression of T cell exhaustion marker Tim-3, however, was upregulated in patients with high frequencies of IL-10-producing B cells. Moreover, supernatant from tumor B cells suppressed T cell inflammation. In addition, frequencies of IL-10-producing tumor-infiltrating B cells were inversely correlated with resected tumor size, and were higher in later stage tumors. Together, our data demonstrated that IL-10-producing B cells had plasmablast-differentiating phenotype, and could contribute to T cell immunosuppression in renal cell carcinoma.
肾细胞癌是癌症相关死亡的主要原因之一，并且被发现可诱导白细胞介素-10（IL-10）产生。我们首先聚焦于肾细胞癌患者肿瘤浸润淋巴细胞中分泌IL-10的细胞，观察到CD3(+) T细胞和CD19(+) B细胞均导致IL-10表达升高。然后我们聚焦于表达IL-10的B细胞，发现与不产生IL-10的B细胞相比，表达IL-10的B细胞CD19和CD20表达水平显著降低，缺乏IgM和IgD表达，而CD27水平升高。此外，在未刺激条件下培养时，这些产生IL-10的B细胞比其外周血对应细胞产生更高水平的抗体，这强烈表明它们是浆母细胞分化细胞。发现了IgA和IgG亚型，但IgA在肿瘤浸润部分中相对丰度更高。然后我们观察到产生IL-10的B细胞频率与产生促炎细胞因子的T细胞及T细胞增殖之间呈负相关。然而，在产生IL-10的B细胞频率高的患者中，T细胞耗竭标志物Tim-3的表达上调。此外，肿瘤B细胞的上清液抑制T细胞炎症。另外，产生IL-10的肿瘤浸润B细胞频率与切除的肿瘤大小呈负相关，并且在晚期肿瘤中更高。总之，我们的数据表明，产生IL-10的B细胞具有浆母细胞分化表型，并可能导致肾细胞癌中的T细胞免疫抑制。
