Poster Presentation MIN Spring Retreat 2023

Uncovering the mechanisms of ovarian damage induced by checkpoint inhibitor immunotherapy (#107)

Lauren R Alesi 1 , Yasmin M Lewis 1 , Amy L Winship 1 , Jessica M Stringer 1 , Shrene Loi 2 , Karla J Hutt 1
  1. Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia
  2. Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

Conventional cancer therapies exert permanent damage to the ovary; hence, fertility loss is a major concern for female reproductive-age cancer survivors1,2. However, attention is shifting to more personalised, targeted treatments3. Immunotherapies — like anti-PD-1/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, but, their impacts on ovarian function and fertility in women are unknown.

We have previously uncovered profound and permanent impacts to ovarian function following checkpoint blockade with anti-PD-L1 and anti-CTLA-4, as evidenced by significant depletion of primordial follicles. Notably, in women, primordial follicle depletion is associated with early loss of fertility and premature menopause.

In the present study, we replicated our previous results using Rag2-/-γc-/- mice, which lack mature T, B and NK cells. These mice were administered anti-PD-L1 or IgG antibodies, with ovaries harvested 21 days later for follicle enumeration. The follicle loss observed in immune-competent C57BL6/J mice at 21 days was abrogated in these immune-deficient mice following checkpoint blockade, with no significant differences observed across all follicle classes. 
Next we assessed follicle numbers in ovaries from wild-type (WT) or Bid-/- mice cultured with or without TNF-α for 4 days. TNF-α led to a significant depletion of primordial follicles in ovaries from WT mice, indicating elevated TNF-α alone is sufficient to deplete primordial follicles. Intriugingly, no primordial follicle loss was observed in TNF-α-treated Bid-/- ovaries. 
Lastly, adult female Bid-/- mice were administered with anti-PD-L1 or control and ovaries harvested 21-days later. Compared to WT mice, anti-PD-L1 treatment exerted no significant impact on any follicle populations, ovulation, or estrous cycling in the Bid-/- mice.

Collectively, these data demonstrate that checkpoint inhibitor-induced ovarian damage is immune cell-mediated. Moreover, BID-mediated apoptosis triggered by elevated TNF-α levels is the likely mechanism of follicle loss induced by these agents.

  1. 1. Bedoschi, G., Navarro, P. A. & Oktay, K. Chemotherapy-induced damage to ovary: mechanisms and clinical impact. Future Oncology 12, 2333-2344, doi:10.2217/fon-2016-0176 (2016).
  2. 2. Duncan, F. E., Kimler, B. F. & Briley, S. M. Combating radiation therapy-induced damage to the ovarian environment. Future Oncology 12, 1687-1690, doi:10.2217/fon-2016-0121 (2016).
  3. 3. Alesi, L. R., Winship, A. L. & Hutt, K. J. Evaluating the impacts of emerging cancer therapies on ovarian function. Current Opinion in Endocrine and Metabolic Research 18, 15-28, doi:10.1016/j.coemr.2020.12.004 (2021).