Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.
Int Immunopharmacol. 2019 Jan;66:127-138. doi: 10.1016/j.intimp.2018.10.045. Epub 2018 Nov 16.
Successful applications of PD-1/PD-L1 blockade in multiple cancers highlight the efficacy of immunotherapy mediated by enhancing CD8 T cell immunity both in mouse and human. How PD-1 blockade affects humoral immunity remains unclear. Herein we demonstrated that treatment of anti-PD-1 antibody led to the increase in both total IgG and OVA-specific IgG in OVA-immunized mice. However, no effect was observed on Ab affinity maturation. Accumulation of germinal center (GC) and memory B cells was observed in the spleens together with elevated percentages of plasma cells in the spleens and bone marrow. More interestingly, dramatic infiltration of CD4 T cells was apparent in GCs after PD-1 blockade with a significant increase in the expression of ICOS. When CD4 T cells and B cells from OVA-immunized mice were co-cultured with neutralizing anti-PD-1 Ab in vitro, PD-1 blockade recapitulated the up-regulation of ICOS expression on CD4 T cells with the activation of ERK signaling. Suppression of ERK activation not only reduced ICOS expression on CD4 T cells but also attenuated IgG production upon PD-1 blockade. Taken together, PD-1 blockade enhances humoral immunity. This process partially relies on more accumulation of CD4 T cells in GCs with the up-regulation of ICOS expression and the promotion of B cell terminal differentiation. The regulatory pattern of PD-1 blockade illustrated here provides a new mechanism of how immune checkpoint molecules regulating humoral immune responses.
PD-1/PD-L1 阻断在多种癌症中的成功应用凸显了通过增强 CD8 T 细胞免疫来介导免疫疗法的疗效，无论是在小鼠还是人类中均如此。然而，PD-1 阻断如何影响体液免疫仍不清楚。在此，我们证明了抗 PD-1 抗体的治疗导致在 OVA 免疫的小鼠中总 IgG 和 OVA 特异性 IgG 均增加。然而，对 Ab 亲和力成熟没有影响。在脾脏中观察到生发中心 (GC) 和记忆 B 细胞的积累，同时脾脏和骨髓中的浆细胞百分比升高。更有趣的是，在 PD-1 阻断后，CD4 T 细胞明显浸润 GC，ICOS 的表达显著增加。当来自 OVA 免疫的小鼠的 CD4 T 细胞和 B 细胞在体外与中和性抗 PD-1 Ab 共培养时，PD-1 阻断再现了 CD4 T 细胞上 ICOS 表达的上调，伴随着 ERK 信号的激活。ERK 激活的抑制不仅降低了 CD4 T 细胞上的 ICOS 表达，而且减弱了 PD-1 阻断后的 IgG 产生。总之，PD-1 阻断增强了体液免疫。这一过程部分依赖于 GC 中 CD4 T 细胞的更多积累，伴随着 ICOS 表达的上调和 B 细胞终末分化的促进。此处所示的 PD-1 阻断的调节模式提供了免疫检查点分子如何调节体液免疫反应的新机制。
