# Targeting the Progesterone Receptor as a Novel Means to Increase Efficacy of Immune Checkpoint Inhibitors in Hormone Receptor Positive Breast Cancer

> **NIH NIH R21** · UNIVERSITY OF KANSAS MEDICAL CENTER · 2022 · $255,588

## Abstract

ABSTRACT
Approximately 75% of all breast cancers (BC) are classified as hormone receptor positive (HR+), the majority
expressing both Estrogen and Progesterone Receptors (ER/PR). Although several classes of anti-estrogen
endocrine therapies exist for these cancers, ~30% of women with ER+ breast cancer develop resistance and
die from metastatic disease. Thus, new therapies are desperately needed for HR+ cancers, which constitute
the majority of deaths from BC. While multiple therapies target ER and ER-signaling pathways, therapies
targeting PR have not yet been employed, as its role in BC remains unclear. Our recent studies have revealed
a significant immune modulatory role for PR in BC. Specifically, our early studies demonstrated a clear role for
PR in suppressing cell intrinsic interferon responses through STAT1/2 inhibition. Recently, using transgenic PR
models and orthotopic mouse PR+ BC lines, we demonstrated that PR expression results in enhanced tumor
development and growth, which is dependent upon adaptive anti-tumor immunity, and altered immune
infiltration into the mammary tumor microenvironment. These findings are congruent with clinical observations
that HR+ BC have a striking reduction of tumor infiltrating lymphocytes in comparison to other BCs and are
less responsive to immune checkpoint inhibitors (ICIs), such as anti-PD-L1 therapy. Thus, our past and current
studies strongly suggest that HR+ BC immunosuppression is mediated by tumor cell PR expression and
immunomodulation of the local tumor microenvironment (TME). We hypothesize that therapeutic targeting of
PR will fundamentally alter the immunosuppressive mammary microenvironment and afford more robust
responses of HR+ BC following treatment with ICIs. We will test this hypothesis in the following Aims: 1)
Determine the anti-tumor utility of anti-progestins with anti-PD-L1 ICI as a means to elicit anti-tumor immunity
against HR+ breast cancer. 2) Determine the anti-tumor utility of an optimal Ad-PR vaccine with anti-PD-L1
ICIs as a means to elicit anti-tumor immunity against HR+ breast cancer. These studies we will determine if
blocking PR can activate localized anti-tumor immunity, thereby sensitizing HR+ breast cancers to treatment
with ICIs. In our first aim, we will determine if anti-progestin blockade of PR signaling can reverse localized
immunosuppression of PR+ mammary tumors and if this approach synergizes with ICI combinations. In our
second aim, we will utilize a novel PR-targeting vaccine to stimulate T cell immunity against PR as a novel
means to drive T cell infiltration into HR+ tumors and invigorate local anti-tumor immunity. The PR vaccine will
be tested alone, and in combination with ICIs, as an additional approach to sensitive these tumors to treatment
with ICIs. If successful, these studies could enable our understanding of PR immune modulation in BC and
allow for new approaches to immunologically treat HR+ BC, which has been refractory to current
immunothera...

## Key facts

- **NIH application ID:** 10512899
- **Project number:** 1R21CA274044-01
- **Recipient organization:** UNIVERSITY OF KANSAS MEDICAL CENTER
- **Principal Investigator:** Christy Hagan
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $255,588
- **Award type:** 1
- **Project period:** 2022-08-24 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10512899

## Citation

> US National Institutes of Health, RePORTER application 10512899, Targeting the Progesterone Receptor as a Novel Means to Increase Efficacy of Immune Checkpoint Inhibitors in Hormone Receptor Positive Breast Cancer (1R21CA274044-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10512899. Licensed CC0.

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