Poster Presentation ESA-SRB-ANZBMS 2024 in conjunction with ENSA

Investigating the long-term impacts of checkpoint immunotherapy on fertility and off-spring health (#421)

Yasmin M Lewis 1 , Jordan Higgins 1 , Amy L Winship 1 , Ngoc TT Nguyen 1 , Kate Rainczuk 1 , Nadeen Zerafa 1 , Karla J Hutt 1
  1. Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia

Immune checkpoint inhibitors (ICIs) are emerging as a prominent therapeutic approach for a diverse range of cancers(1-3). ICIs enhance a patient’s immune response against malignant cells, but can also induce immune-related off-target side effects, such as pneumonitis and myocarditis(4,5).

Our pre-clinical studies in mice have revealed that off-target effects extend to the ovary. Notably, ICI monotherapy led to depletion of primordial follicles, increased follicular atresia, impaired ovulation and reduced oocyte quality(6). However, it is unknown if fertility is impaired in ICI-treated mice, or whether ICI treatment compromises off-spring development or health.

To investigate the reproductive capacity and off-spring health of ICI-treated mice, 8-week-old C57BL6 females (n=12/treatment) were treated a clinically relevant regimen of anti-PD-L1 or IgG control antibodies (on days 1, 4, 8 & 11). Females were then paired with untreated fertile males 49 days after the final dose. Litter size, frequency, and off-spring weight were monitored throughout the breeding trial.

The number of pups per litter and frequency of litters did not differ between ICI-treated and control females. Furthermore, no differences in weight were observed in offspring at post-natal day (PN) 5. However, off-spring from anti-PD-L1 treated females weighed significantly less at weaning (PN20) than off-spring from control females. The reduced off-spring weight at weaning may differences in nursing behaviour or altered milk composition in females treated with anti-PD-L1.

These early data suggest that immune checkpoint blockade does not reduce the ability of females to produce off-spring. Additionally, although immune-checkpoint blockade does not seem to impair off-spring development in utero or neonatally, it does disrupt post-natal growth, which could have significant implications for future health. Further research is essential to fully understand the long-term consequences of these findings and to develop strategies to mitigate any potential adverse effects on offspring health.

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  4. Axelrod ML, Meijers WC, Screever EM, Qin J, Carroll MG, Sun X, et al. T cells specific for alpha-myosin drive immunotherapy-related myocarditis. Nature. 2022;611(7937):818-26.
  5. Suresh K, Naidoo J, Zhong Q, Xiong Y, Mammen J, de Flores MV, et al. The alveolar immune cell landscape is dysregulated in checkpoint inhibitor pneumonitis. J Clin Invest. 2019;129(10):4305-15.
  6. Winship AL, Alesi LR, Sant S, Stringer JM, Cantavenera A, Hegarty T, et al. Checkpoint inhibitor immunotherapy diminishes oocyte number and quality in mice. Nat Cancer. 2022;3(8):1-13