Effects of PD-1 blockade on ovarian follicles in a prepubertal female mouse

in Journal of Endocrinology
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  • 1 Olson Center for Women’s Health, Department of Obstetrics and Gynecology, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska
  • | 2 Division of Reproductive and Developmental Sciences, Oregon National Primate Research Center, Beaverton, Oregon
  • | 3 Department of Obstetrics and Gynecology, School of Medicine, Oregon Health & Science University, Portland, Oregon
  • | 4 Division of Pediatric Hematology/Oncology, Department of Pediatrics, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska

Correspondence should be addressed to S-Y Kim: soyoun.kim@unmc.edu
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Immunotherapy has emerged at the forefront of cancer treatment. Checkpoint inhibitor pembrolizumab (KEYTRUDA), a chimeric antibody which targets programmed cell death protein 1 (PD-1), has been approved by the Food and Drug Administration (FDA) for use in pediatric patients with relapsed or refractory classical Hodgkin’s lymphoma. However, there is currently no published data regarding the effects of pembrolizumab on the ovary of female pediatric patients. In this study, prepubertal immunocompetent and immunodeficient female mice were injected with pembrolizumab or anti-mouse PD-1 antibody. The number of primordial follicles significantly decreased post-injection of both pembrolizumab and anti-mouse PD-1 antibody in immunocompetent mice. However, no changes in follicle numbers were observed in immunodeficient nude mice. Superovulation test and vaginal opening experiments suggest that there is no difference in the number of cumulus–oocyte complexes (COCs) and the timing of puberty onset between the control and anti-mouse PD-1 antibody treatment groups, indicating that there is no effect on short-term fertility. Elevation of pro-inflammatory cytokine TNF-α following COX-2 upregulation was observed in the ovary. CD3+ T-cell infiltration was detected within some ovarian follicles and between stromal cells of the ovaries in mice following treatment with anti-mouse PD-1 antibody. Thus, PD-1 immune checkpoint blockade affects the ovarian reserve through a mechanism possibly involving inflammation following CD3+ T-cell infiltration.

Supplementary Materials

    • Table S1. List of primer sequences
    • Table S2. List of primary antibodies
    • Supplemental Figure S1. Pembrolizumab treatment depletes primordial follicles within 48 hours of initial treatment in immunocompetent mice. A. Bilateral kidney weight, liver weight, and pancreas weight following two treatment cycles of Fc or pembrolizumab. B. Additional inset images of primordial (Pr), primary (Pm), secondary (Sec), and antral (AF) follicle histology. C. Treatment cycle schematic for saline, Fc, and pembrolizumab (pemb) injection in CD-1® IGS immunocompetent mice starting at postnatal day 13. D. Body weights of mice 7 days post initial treatment with Fc or pembrolizumab. E. Follicle counts 7 days post initial treatment for each class of follicles in ovaries of mice injected with Fc or pembrolizumab. F. Spleen weight, bilateral kidney weight, liver weight, and pancreas weight of mice 48 hours post initial treatment with mouse IgG or 2x mPD-1. G. Body weight of mice 48 hours post initial treatment with saline, mouse IgG, and 1x or 2x mPD-1.
    • Supplemental Figure S2. Specific epitope binding of CD3, PD-1, and PD-L1 antibodies. A. Positive control immunohistochemical and immunofluorescence images of CD3 expression in lymph node tissue sections from a GEMM of granulosa cell tumors. Nuclei are stained with DAPI. Scale bar = 50 or 150 µm. B. Additional positive control immunohistochemical images of PD-1 expression in lymph node tissue sections from a GEMM of granulosa cell tumors. Scale bar = 50 µm. C. Additional positive control immunohistochemical images PD-L1 expression in tumor tissue sections from a GEMM of pancreatic ductal adenocarcinoma. Scale bar = 150 µm.

 

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