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

Abstract

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 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 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.

Expression and T cell regulatory action of the PD‐1 immune checkpoint in the ovary and fallopian tube

“…We show herein that membrane bound and soluble PD‐1 pathway receptor and ligand proteins are expressed in resident (non‐lymphoid/non‐myeloid) cells of the human ovary, and can be found in the fluid collected from peri‐ovulatory follicles during IVF retrieval procedures. These data are reminiscent of one of our group's prior findings evaluating PD‐1 pathway expression and function in a mouse model where follicle numbers were evaluated after antibody (pembrolizumab) PD‐1 blockade 29 …”

“…32,39,40 STIC cells detach from the tubal lumen and engraft at distant sites within the peritoneum, including the surface of the ovary at ovulation site(s). 41,42 During a preliminary evaluation of Pd-1 pathway protein expression in the mouse ovary, we detected broad expression of the receptor and ligands in the organ, in somatic immune and non-immune cells and oocytes (consistent with 29 ). There was also an existing report in a publicly-available large-scale gene expression screen (LifeMap Discovery) that showed that PD-1 pathway transcripts are detectable in human cumulus granulosa cells (HCGC).…”

“…28 Information is now available about expression and function of the pathway in normal ovarian cell types, and in mouse models, blockade of PD-1 signaling in the absence of cancer has been shown to compromise the reserve of ovarian follicles. 29,30 The most common histotype of EOC is high grade serous ovarian cancer (HGSOC). The originating cells of HGSOC are increasingly thought to be transformed fallopian tube epithelial (FTE) cells.…”

“…Notably, EOC is considered an immunogenic disease, 27 but the response rate to checkpoint inhibitor immunotherapies has been unexpectedly low 28 . Information is now available about expression and function of the pathway in normal ovarian cell types, and in mouse models, blockade of PD‐1 signaling in the absence of cancer has been shown to compromise the reserve of ovarian follicles 29,30 …”

Primary ovarian insufficiency secondary to chemotherapy with inotuzumab ozogamicin and other agents

“…A 2021 study of checkpoint inhibitor pembrolizumab in a prepubertal mouse model found that PD-1 checkpoint blockade affects the ovarian reserve through a mechanism possibly involving inflammation-mediated follicle depletion. In contrast to IO, PDL-1 expression, the target antigen of pembrolizumab, was demonstrated in the murine ovary [ 20 ]. These findings support the role of either a direct effect of anti-PDL-1 treatment or resultant inflammatory responses on ovarian function.…”