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-1, 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 intra-ovarian CD4+ (1003±76 versus control 632±53; p=0.007) and CD8+ T cells (1072±129 versus control 628±58; p=0.02) and TNF-α cytokine production. Disruptions to folliculogenesis and ovulation were observed, with a significant 117% increase in antral follicle atresia (90±20.7, versus control 41.4±10.5; p=0.04) and reduction in corpora lutea (2.4±0.4, versus control 5±0.4, p=0.003), 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 ovarian reserve of primordial follicles by 43% and 38% respectively (1031±161 and 1116±247 versus control 1809±167, p<0.05) after 21 days. Notably, in women, primordial follicle depletion is associated with early loss of fertility and premature menopause. Furthermore, the number ovulated oocytes was significantly reduced following anti-CTLA-4 treatment (25±3, versus control 34±2; p=0.03), whereas anti-PD-L1 increased the number of fragmented/dead oocytes (8±2, versus control 2±1; p=0.03).
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.