# Stress-induced immunosuppression via downregulation of interferon in triple negative breast cancer

> **NIH NIH K08** · EMORY UNIVERSITY · 2024 · $156,562

## Abstract

PROJECT SUMMARY
Triple negative breast cancer (TNBC) is the most aggressive form of breast cancer (BC) which occurs more
frequently in younger women, often diagnosed once the disease has already metastasized. It is the only BC
subtype where immune checkpoint inhibitors (ICIs) are approved for use, but only a minority of patients respond
to current ICI treatments. One mechanism of resistance is low expression of intratumoral chemokines CXCL9
and CXCL10, essential for attracting anti-tumor CD8+ T cells into the tumor microenvironment (TME).
Psychosocial stress, experienced by many BC patients can enhance immunosuppression. β-adrenergic receptor
blockade has shown higher survival benefit in TNBC patients compared with other BC subtypes (observational
studies), suggesting a possibility of sympathetic overdrive in TNBC. However, the mechanistic role of
psychosocial stress in treatment resistance to ICIs among TNBC patients remains unknown. We have shown
that chronic stress and its mediators, epinephrine (EPI) and norepinephrine (NE), drive immunosuppression in
the TME by decreasing CD8+ T cells and increasing myeloid derived suppressor cells and regulatory T cells. Our
subsequent study showed that propranolol, a pan-β-blocker, improves response to ICIs in metastatic melanoma
patients. We also found that EPI can mediate the induction of prostaglandin E2 (PGE2) in BC tissues. We and
others have shown that PGE2 inhibits interferon (IFN)-induced CXCL9/10 secretion. Thus, I hypothesize that
chronic stress promotes immunosuppression in TNBC by increasing PGE2 and inhibiting IFN pathways, resulting
in decreased CXCL9/10. I propose to test this hypothesis in the following aims: 1) Examine NE-induced changes
in TNBC tissues and test therapeutic measures ex vivo; 2) Study immune changes in pre- vs. post-treatment
tumor tissues and blood of metastatic TNBC patients receiving propranolol and ICI; and 3) Correlate validated
measures of psychosocial stress with the expression of IFNs and CXCL9/10 in BC tissues. To achieve these
goals, I will utilize TNBC tissues from patients in ex vivo studies, conduct a prospective clinical trial, and examine
relationships between self-reported stress and correlates of tumor immunity in banked samples. To gain
mechanistic understanding, complementary state-of-the-art multiplex tissue imaging techniques including
confocal microscopy, imaging mass cytometry, and spatial transcriptomics will be utilized. Completion of the
proposed work will provide key novel insights into the mechanistic role of the PGE2-IFN-chemokines pathway in
stress-induced TME immunosuppression and help inform new approaches that will be translated into enhanced
therapeutic benefit for TNBC patients. This project will advance my development into an independent clinical
scientist and translational researcher advancing precision immuno-oncology treatments for TNBC. This will be
accomplished in a rich academic environment at Roswell Park Comprehensive Cancer Cente...

## Key facts

- **NIH application ID:** 11287201
- **Project number:** 7K08CA279766-02
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Shipra Gandhi
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $156,562
- **Award type:** 7
- **Project period:** 2024-07-01 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11287201

## Citation

> US National Institutes of Health, RePORTER application 11287201, Stress-induced immunosuppression via downregulation of interferon in triple negative breast cancer (7K08CA279766-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/11287201. Licensed CC0.

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