Poster Presentation Melbourne Immunotherapy Network Winter Symposium 2021

Checkpoint inhibitor immunotherapy diminishes oocyte number and quality in tumour-free mice: consequences for fertility of female cancer survivors (#124)

Lauren R Alesi 1 , Amy L Winship 1 , Sneha Sant 2 , Jessica M Stringer 1 , Teharn Hegarty 1 , Meaghan J Griffiths 1 , Sherene Loi 2 , Karla J Hutt 1
  1. Ovarian Biology Laboratory, Monash Biomedicine Discovery Institute, Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia
  2. Division of Clinical Medicine and Research, Sir Peter MacCallum Department of Oncology, Peter MacCallum Cancer Centre, University of Melbourne, Parkville, VIC, Australia

Women are born with their entire supply of oocytes stored in primordial follicles, which cannot be replenished once depleted1. Conventional cytotoxic cancer therapies exert permanent damage to the ovary by depleting primordial follicles2,3. Therefore, 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 cells4. 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-L1 and anti-CTLA-4 antibodies on the ovary in tumour-free mice, with profound and permanent impacts to ovarian function observed. After 21 days, PD-L1 and CTLA-4 blockade induced significant depletion of primordial follicles by 43% and 38% respectively (1031±161 and 1116±247 versus control 1809±167, p<0.05). Notably, in women, primordial follicle depletion is associated with early loss of fertility and premature menopause. Proportions of cleaved caspase-3-positive ovarian follicles were increased by 76% and 59% after anti-PD-L1 and anti-CTLA-4 treatment respectively (35.9±3.7% and 32.4±3.4% versus control 17.9±3.0%, p<0.01), suggesting that checkpoint inhibition induces follicular apoptosis. TNF-α can trigger extrinsic apoptosis via death receptor signalling, and induces apoptosis of follicular cells in vitro5,6. Interestingly, both intra-ovarian TNF-α production (5.6±1.6 and 6.4±1.9 versus control 1.0±0.09, p<0.05) and circulating TNF-α levels were elevated after PD-L1 and CTLA-4 inhibition, suggesting that increased TNF-α levels may contribute to checkpoint inhibitor-mediated ovarian dysfunction.

Collectively, these data demonstrate that immune checkpoint inhibitors may impair the fertility of young female cancer survivors. Hence, fertility preservation should be strongly considered for women receiving these immunotherapies, and investigation of preventative strategies must be prioritised in future studies.

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