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785 Estrogen-deprivation promotes Th1 polarization of tumor-associated T cells in a mouse model of high grade serous ovarian cancer
  1. Daniel Falcon,
  2. Marina Miller,
  3. Chelsea Goff,
  4. Ichiko Kinjyo and
  5. Sarah Adams
  1. University of New Mexico, Albuquerque, NM, USA


Background Immunotherapy has achieved long-term survival in patients with melanoma and other tumors, introducing a new paradigm in cancer treatment. Differential outcomes among men and women receiving immune checkpoint inhibitors implicate sex steroids as modulators of treatment response. Estrogen signaling has a profound impact on T cell function and has been shown to upregulate FoxP3 expression, promoting a suppressive regulatory phenotype. Conversely, estrogen deprivation promotes Th1 skewing, including increased IFN-γ production in response to antigen-specific stimulation. We hypothesize that immunomodulatory effects of estrogen deprivation will enhance immunotherapy outcomes.

Our lab has previously demonstrated that IFN-γ levels in the TME predict response to immune checkpoint blockade (ICB) regimens in ovarian cancer models. CTLA4 but not PD1/PDL1 ICB combined with PARP inhibition (PARPi), an oral chemotherapeutic, significantly increased IFN-γ in the TME. Furthermore, IFN-γ was required for the durable survival benefit achieved with PARPi/anti-CTLA4. Here we test whether estrogen deprivation enhances IFN-γ production in the TME and response to PARPi/anti-PD1.

Methods Five-week-old female FVB mice underwent oophorectomy, laparotomy without oophorectomy (sham), or no surgery (n = 5 per group). On day 10, mice were intraperitoneally challenged with 200,000 BR5-Akt syngeneic OC cells and randomly assigned to receive either PARPi/anti-CTLA4, PARPi/anti-PD1 or vehicle control treatment. PARPi (40mg/kg/day) was administered days 13-30 and 100 μg of anti-CTLA4 or 300 μg anti-PD1 was administered on D14. A second dose of anti-PD1 was given on D24. On day 30, peritoneal cells were analyzed by flow cytometry. Tumor burden was measured by IVIS.

Results Oophorectomy was associated with a significant increase in IFN-γ production by tumor-associated CD4+ T cells [30.4% vs 8.2%, p = 0.016] and an increase in the proportion of central memory CD8+ T cells [59.3% vs 34.9%, p = 0.007] in response to PARPi/anti-PD1 compared with sham and no-surgery controls. In contrast, no differences in T cell phenotype or function was noted among groups receiving PARPi/anti-CTLA4. These changes were associated with a decrease in tumor burden in response to PARPi/anti-PD1 on D30.

Conclusions Estrogen deprivation promotes Th1 polarization among tumor-associated T cells in response to PARPi/anti-PD1 treatment. With evidence that high levels of IFN-γ in the TME strongly correlate with survival, we predict that these effects will enhance treatment outcomes in response to PARPi/anti-PD1. This work presents a rationale for testing estrogen receptor modulators in combination with immune therapy agents and provides a potential mechanism to account for observed differences in patient outcomes.

This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See:

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