# Adipocyte PD-L1 in the Breast Tumor Microenvironment

> **NIH NIH R01** · GEORGE WASHINGTON UNIVERSITY · 2024 · $675,405

## Abstract

ABSTRACT
 Programmed death-ligand 1 (PD-L1) and its receptor, programmed cell death protein 1 (PD-1), modulate
anti-tumor immunity and are major targets of current checkpoint blockade immunotherapies. However,
clinical trials of αPD-L1/αPD-1 antibodies in breast cancer to date have demonstrated only limited efficacy. The
importance of a breast-specific tumor microenvironment (TME) in regulating anti-tumor immunity is vastly under-
explored. Given the abundance of adipocytes in breast tissue, the well-documented association between
adiposity and breast cancer-related mortality, and the emerging obesity paradox in anticancer immunotherapy, it
is imperative to investigate the molecular underpinnings of the complex adipose-immune-tumor network within
the adipocyte-rich breast TME.
 We recently identified a previously unappreciated, functionally significant source of PD-L1 in white
adipocytes. Adipocyte PD-L1 is markedly induced during adipogenesis and obesity-related chronic
inflammation. Using an adipocyte-specific knockout mouse model, we demonstrate an important role of
adipocyte PD-L1 in promotion of tumor growth and attenuation of anti-tumor immunity. Furthermore, our
preliminary data indicate physical and functional interactions between PD-L1 and lipid metabolism-related proteins
and pathways in adipocytes, which suggests an adipocyte-intrinsic function of PD-L1. Based on our preliminary
data, we hypothesize that adipocyte PD-L1 impedes anti-tumor lymphocytes and/or abets tumor cells through
a lipid metabolism-related mechanism. We further propose that this action of adipocyte PD-L1 is particularly
important at the tumor margin of immune-excluded tumors, where adipocytes are in proximity with both tumor
and immune cells. We will combine our established tools and expertise in cancer biology, tumor immunology,
and transcriptional regulation to validate this novel hypothesis through the following Aims: (1) Delineate how
adipocyte PD-L1 mediates adipose-immune-tumor crosstalk, (2) Determine how adipocyte PD-L1 expression
is regulated, and (3) Determine how adipocyte PD-L1 impacts immunotherapy in obese vs non-obese hosts.
 Our studies on adipocyte PD-L1 signaling in lipid metabolism will provide new molecular explanations for
PD-L1 action in tumor immunology, a clear departure from the prevailing paradigm regarding tumor/immune
PD-L1 actions. This proposed work represents a conceptual advance toward understanding the spatial
landscape of the breast TME in immune regulation and tumorigenesis – a clinically relevant yet mechanistically
under-explored problem. Our results could lay a solid foundation for developing new tools that predict and
enhance therapeutic response to aPD-1/aPD-L1 immunotherapy for breast cancer patients, especially those
with obesity.

## Key facts

- **NIH application ID:** 10882100
- **Project number:** 1R01CA279566-01A1
- **Recipient organization:** GEORGE WASHINGTON UNIVERSITY
- **Principal Investigator:** Tyler J. Curiel
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $675,405
- **Award type:** 1
- **Project period:** 2024-04-01 → 2029-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10882100

## Citation

> US National Institutes of Health, RePORTER application 10882100, Adipocyte PD-L1 in the Breast Tumor Microenvironment (1R01CA279566-01A1). Retrieved via AI Analytics 2026-06-05 from https://api.ai-analytics.org/grant/nih/10882100. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*