Checkpoint Inhibitor Immunotherapy Diminishes Oocyte Number And Quality: Consequences For Fertility Of Female Cancer Survivors
Conventional cytotoxic cancer therapies exert permanent damage to the ovary; hence, loss of fertility is a major concern for female reproductive-age cancer survivors. However, the landscape of cancer therapies is rapidly changing, with attention shifting to more personalised, targeted treatments. Immunotherapies, like checkpoint inhibitors anti-PD-L1 and anti-CTLA-4, harness the immune system to kill tumour cells. They are increasingly becoming a standard of care for many tumour types, including in the curative setting. But, their impacts on ovarian function and fertility are unknown. We evaluated the effect of anti-PD-1, anti-PD-L1 and anti-CTLA-4 antibodies on the ovary using tumour-bearing and tumour-free mouse models. In tumour bearing mice, combination immune checkpoint inhibition (anti-PD-1 + anti-CTLA-4) increased recruitment of CD4+ and CD8+ T cells to the ovary, and increased local TNF-α cytokine production. Disruptions to ovarian function were observed, with increased death (atresia) of pre-ovulatory ovarian follicles and fewer corpora lutea present (indicating reduced ovulations). Profound and permanent impacts to ovarian function were also detected in tumour-free mice. PD-L1 or CTLA-4 blockade induced significant depletion of the non-renewable supply of primordial follicles (containing immature oocytes). Notably, in women, primordial follicle depletion is associated with early loss of fertility and premature menopause. Furthermore, the number of healthy, mature ovulated oocytes was significantly reduced following anti-CTLA-4 treatment, whereas anti-PD-L1 increased the number of fragmented/dead oocytes. Collectively, these data demonstrate that immune checkpoint inhibitors have the potential to impair both the immediate and future fertility of young women. Hence, fertility preservation should be strongly considered for women receiving these immunotherapies, and investigation of preventative strategies must be prioritised in future studies.