School of Biology & Basic Medical Sciences, Medical College of Soochow University, Suzhou, China.
Department of Pathology, The First People's Hospital of Lianyungang, Lianyungang, China.
Front Immunol. 2022 Jul 22;13:830606. doi: 10.3389/fimmu.2022.830606. eCollection 2022.
Accumulating evidence suggests that regulatory B cells (Bregs) play important roles in inhibiting the immune response in tumors. Programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1) are important molecules that maintain the balance of the immune response and immune tolerance. This study aims to evaluate the soluble form of PD-L1 and its function in inducing the differentiation of B lymphocytes, investigate the relationship between soluble PD-L1 (sPD-L1) and B-cell subsets, and explore the antitumor activity of T lymphocytes after PD-L1 blockade in coculture systems. In an effort to explore the role of sPD-L1 in human breast cancer etiology, we examined the levels of sPD-L1 and interleukin-10 (IL-10) in the serum of breast tumor patients and the proportions of B cells, PD-1 B cells, Bregs, and PD-1 Bregs in the peripheral blood of patients with breast tumors and assessed their relationship among sPD-L1, IL-10, and B-cell subsets. The levels of sPD-L1 and IL-10 in serum were found to be significantly higher in invasive breast cancer (IBCa) patients than in breast fibroadenoma (FIBma) patients. Meanwhile, the proportions and absolute numbers of Bregs and PD-1 Bregs in the peripheral blood of IBCa patients were significantly higher than those of FIBma patients. Notably, they were the highest in triple-negative breast cancer (TNBC) among other subtypes of IBCa. Positive correlations of sPD-L1 and IL-10, IL-10 and PD-1 Bregs, and also sPD-L1 and PD-1 Bregs were observed in IBCa. We further demonstrated that sPD-L1 could induce Breg differentiation, IL-10 secretion, and IL-10 mRNA expression in a dose-dependent manner . Finally, the induction of regulatory T cells (T) by Bregs was further shown to suppress the antitumor response and that PD-L1 blockade therapies could promote the apoptosis of tumor cells. Together, these results indicated that sPD-L1 could mediate the differentiation of Bregs, expand CD4 T and weaken the antitumor activity of CD4 T cells. PD-L1/PD-1 blockade therapies might be a powerful therapeutic strategy for IBCa patients, particularly for TNBC patients with high level of PD-1 Bregs.
越来越多的证据表明调节性 B 细胞 (Bregs) 在抑制肿瘤中的免疫反应中发挥重要作用。程序性死亡受体 1 (PD-1) 和程序性死亡配体 1 (PD-L1) 是维持免疫反应和免疫耐受平衡的重要分子。本研究旨在评估可溶性 PD-L1 (sPD-L1) 的功能及其诱导 B 淋巴细胞分化的能力，研究 sPD-L1 与 B 细胞亚群的关系，并探讨 PD-L1 阻断在共培养系统中对 T 淋巴细胞抗肿瘤活性的影响。为了探讨 sPD-L1 在人乳腺癌发病机制中的作用，我们检测了乳腺癌患者血清中 sPD-L1 和白细胞介素 10 (IL-10) 的水平，以及乳腺癌患者外周血中 B 细胞、PD-1+B 细胞、Bregs 和 PD-1+Bregs 的比例，并评估了它们之间的关系。结果发现，浸润性乳腺癌 (IBCa) 患者血清中 sPD-L1 和 IL-10 的水平明显高于乳腺纤维腺瘤 (FIBma) 患者。同时，IBCa 患者外周血中 Bregs 和 PD-1+Bregs 的比例和绝对数量明显高于 FIBma 患者，其中三阴性乳腺癌 (TNBC) 患者最高。IBCa 患者中 sPD-L1 和 IL-10、IL-10 和 PD-1+Bregs 以及 sPD-L1 和 PD-1+Bregs 呈正相关。我们进一步证明 sPD-L1 可以剂量依赖性地诱导 Breg 分化、IL-10 分泌和 IL-10 mRNA 表达。最后，还进一步表明 Bregs 诱导的调节性 T 细胞 (T) 抑制抗肿瘤反应，而 PD-L1 阻断疗法可促进肿瘤细胞凋亡。综上所述，这些结果表明 sPD-L1 可以介导 Bregs 的分化，扩增 CD4 T 细胞，并减弱 CD4 T 细胞的抗肿瘤活性。PD-L1/PD-1 阻断疗法可能是 IBCa 患者，特别是 PD-1+Bregs 水平较高的 TNBC 患者的一种强有力的治疗策略。
