Laboratory for Reproductive Immunology, NHC Key Lab of Reproduction Regulation(Shanghai Institute of Planned Parenthood Research), Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Hospital of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai, P.R. China.
Reproductive Medicine Center, Hospital of Obstetrics and Gynecology, FudanUniversity Shanghai Medical School, Shanghai, P.R. China.
Cell Death Dis. 2019 Jan 8;10(1):15. doi: 10.1038/s41419-018-1251-0.
The single and/or combination use of immune checkpoint blockade therapies in human infectious diseases and cancer are rapidly expanding. Despite early efforts, substantial uncertainty remains about the safety and efficacy of immune checkpoint blockade in some populations. Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and T-cell immunoglobulin mucin-3 (Tim-3) are the major targetable co-inhibitory receptors on T cells. Here we showed that in animal studies, treatment with either CTLA-4- or Tim-3-blocking antibody caused greater susceptibility to fetal loss with altered cytokine profiles by decidual CD4T (dCD4T) cells. CTLA-4 and Tim-3 pathways appeared to play key roles in maintaining maternal-fetal tolerance by regulating the function of dCD4T cells. In addition, the abnormality in number and functionality of dCTLA-4Tim-3CD4T cells was associated with miscarriage. These findings underscored the important roles of the CTLA-4 and Tim-3 pathways in regulating dCD4T cells function and maintaining normal pregnancy. Our study also emphasized the importance of careful consideration of reproductive safety when choosing immune checkpoint blockade therapies in real world clinical care.
免疫检查点阻断疗法在人类传染病和癌症中的单一和/或联合应用正在迅速扩展。尽管早期做了很多努力，但在某些人群中，免疫检查点阻断的安全性和有效性仍然存在很大的不确定性。细胞毒性 T 淋巴细胞相关蛋白 4（CTLA-4）和 T 细胞免疫球蛋白粘蛋白 3（Tim-3）是 T 细胞上主要的可靶向共抑制受体。在这里，我们发现在动物研究中，用 CTLA-4 或 Tim-3 阻断抗体治疗会导致胎儿丢失的易感性增加，并通过蜕膜 CD4T（dCD4T）细胞改变细胞因子谱。CTLA-4 和 Tim-3 通路似乎通过调节 dCD4T 细胞的功能在维持母胎耐受中发挥关键作用。此外，dCTLA-4Tim-3CD4T 细胞数量和功能的异常与流产有关。这些发现强调了 CTLA-4 和 Tim-3 通路在调节 dCD4T 细胞功能和维持正常妊娠中的重要作用。我们的研究还强调了在现实世界的临床护理中选择免疫检查点阻断疗法时，需要仔细考虑生殖安全性的重要性。
