# Ceramide metabolism and the regulation of PD-L1 signaling to control metastasis and resistance to immunotherapy in TNBC

> **NIH NIH R01** · MEDICAL UNIVERSITY OF SOUTH CAROLINA · 2024 · $352,520

## Abstract

SUMMARY
Metastasis is a significant cause of mortality for patients with triple-negative breast cancer (TNBC), with a median
overall survival of less than one year. The introduction of immunotherapy has revolutionized the systemic
treatment of metastatic cancer. However, there are underlying resistance mechanisms that limit response to
immunotherapy in TNBCs. Increased PD-L1 cell surface expression is associated with improved response to α-
PD-L1 or α-PD-1 therapies. One potential mechanism by which tumor cells acquire resistance to immunotherapy
is by reducing PD-L1 expression in the cell membrane. Furthermore, recent reports have demonstrated that
internalized (non-membranous) PD-L1 participates in oncogenic/pro-metastatic signaling within cancer cells
without much mechanistic understanding. It is known that lipid metabolism and signaling alterations play a role
in cancer cell migration/invasion and tumor metastasis, including reductions of bioactive sphingolipid ceramide
that mediates pro-apoptotic and anti-proliferative signaling. We recently showed that reductions in ceramide
synthase 4 (CerS4)-generated long-chain C18-C20-ceramides induce TNBC migration and metastasis by
activating the TGF-β/Sonic hedgehog (Shh) signaling axis. However, the regulatory components of this
mechanism remain unknown. Based on our published and unpublished preliminary data, this application is
designed to test a novel overall hypothesis that the reduction of CerS4-generated ceramide signaling enhances
PD-L1 internalization, induces pro-metastatic signaling and facilitates resistance to immunotherapy in
TNBC. There are two Specific Aims proposed: Aim 1 is designed to define the mechanism by which reduced
CerS4/ceramide signaling regulates PD-L1 internalization and its intracellular metastatic signaling. Aim 2 is
designed to determine how CerS4/ceramide signaling regulates the PD-L1/Caprin-1 complex to control TNBC
metastasis and resistance to immunotherapy. Overall, this application describes a novel resistance mechanism
to immunotherapy and intracellular PD-L1-dependent pro-metastatic signaling driven by lipid/ceramide
metabolism alterations. Combination therapies targeting this signaling network could reduce the metastatic
burden and improve metastatic TNBC response to immunotherapy, collectively addressing clinically unmet
needs in this application.

## Key facts

- **NIH application ID:** 10932439
- **Project number:** 5R01CA214461-07
- **Recipient organization:** MEDICAL UNIVERSITY OF SOUTH CAROLINA
- **Principal Investigator:** Besim Ogretmen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $352,520
- **Award type:** 5
- **Project period:** 2018-08-31 → 2028-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10932439

## Citation

> US National Institutes of Health, RePORTER application 10932439, Ceramide metabolism and the regulation of PD-L1 signaling to control metastasis and resistance to immunotherapy in TNBC (5R01CA214461-07). Retrieved via AI Analytics 2026-08-17 from https://api.ai-analytics.org/grant/nih/10932439. Licensed CC0.

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