Abstract
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 CD4+T (dCD4+T) cells. CTLA-4 and Tim-3 pathways appeared to play key roles in maintaining maternal-fetal tolerance by regulating the function of dCD4+T cells. In addition, the abnormality in number and functionality of dCTLA-4+Tim-3+CD4+T cells was associated with miscarriage. These findings underscored the important roles of the CTLA-4 and Tim-3 pathways in regulating dCD4+T 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.
Highlights
T cell activation following antigen recognition requires a secondary co-stimulatory signal, which can be either positive or negative
Cytotoxic T-lymphocyteassociated protein 4 (CTLA-4) had a role in both early and late stages of T cell activation and was mainly expressed on T cells residing in lymph nodes[5], while T-cell immunoglobulin mucin-3 (Tim-3) could exert its function by regulating cell apoptosis[6], so the combination of anti
Effects of dual blockade of CTLA-4 and Tim-3 on mouse pregnancy In the first assay, we examined pregnant CBA/J females challenged with CTLA4- and/or Tim-3-blocking antibody
Summary
T cell activation following antigen recognition requires a secondary co-stimulatory signal, which can be either positive or negative. Cytotoxic T-lymphocyteassociated protein 4 (CTLA-4), programmed death 1 (PD-1), and T-cell immunoglobulin mucin-3 (Tim-3) are. The development of these immunotherapy agents has increased since the first approval of anti-CTLA-4 therapy (ipilimumab) by the United States Food and Drug Administration for melanoma in 20112. Despite their success, the single use of currently approved antibodies was effective in only 20–30% of patients[3]. CTLA-4 had a role in both early and late stages of T cell activation and was mainly expressed on T cells residing in lymph nodes[5], while Tim-3 could exert its function by regulating cell apoptosis[6], so the combination of anti-
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