# Metabolic Regulation ofPD-L1 in CD11c+ Cells

> **NIH NIH R01** · INDIANA UNIVERSITY INDIANAPOLIS · 2022 · $520,593

## Abstract

Project Summary/Abstract
The long-term goal is to find better intervening approaches to interdict cancer initiation, progression and
metastasis. The PD-L1/PD-1 signaling pathway is a critical immune checkpoint mechanism utilized by tumor to
escape antitumor immune responses. PD-L1 binds to PD-1 on activated T cells to mediate an inhibitory signal
through PD-1-expressing T cells. In comparison, the functional roles of PD-L1 expression in the myeloid
compartment are less clear. CD11c+ DCs are well known for their function to capture tumor antigens and
cross-present these antigens to T cells in tumor-draining lymph nodes, resulting in the generation of
tumor-specific cytotoxic T lymphocytes (CTLs) that contribute to tumor rejection. Interestingly, we have shown
that CD11c+ cells isolated from the blood of lysosomal acid lipase (LAL) knockout (lal-/-) mice possess
immunosuppression in the absence of antigen presentation, and directly stimulate tumor proliferation in vitro and
tumor growth in vivo. Concomitantly, PD-L1 expression was increased in lal-/- CD11c+ cells, which is required for
immunosuppression and tumor stimulation. Our observations suggest that the LAL deficiency-induced metabolic
switch leads CD11c+ cells to confer tumor stimulation rather than rejection. Based on these observations, this
proposal will focus on how PD-L1 expression in lal-/- CD11c+ cells contributes to immune suppression and tumor
stimulation during LAL-deficiency. LAL is a key enzyme that hydrolyzes cholesteryl esters and triglycerides in
the lysosome of cells to generate free fatty acids (FFAs) and cholesterol. The metabolites of FFAs are ligands for
nuclear transcription factor peroxisome proliferator activated receptor  (PPAR), a negative regulator of
inflammation. Since LAL is critically involved in fatty acid metabolism, the proposed study will further elucidate
the underneath metabolic mechanism by which lal-/- CD11c+ cells influence tumor immunity and stimulation
through PD-L1 expression. RNAseq and flow cytometry demonstrated that PD-L1 expression is regulated by
glucose/glutamine metabolic processes and mammalian target of rapamycin (mTOR) in lal-/- CD11c+ cells, which
is under the control of PPAR. Therefore, the current proposal will test a central hypothesis that
LAL/PPAR/mTOR axis-regulated PD-L1 expression plays a key role in lal-/- CD11c+ cells’ immune suppression
and tumor stimulation through metabolic reprogramming. To achieve our goals, we will use the unique lal-/-
mouse model and the conditional c-fms-rtTA/(TetO)7-CMV-hLAL;lal-/- triple mouse model (c-fms-Tg/KO) in which
hLAL is specifically expressed in the myeloid compartment of lal-/- mice. The following specific aims are designed
to test the central hypothesis:1) Characterizing the developmental and metabolic regulation of PD-L1 expression
in CD11c+ cells; 2) Characterizing PD-L1 expression of CD11c+ cells in regulating T cell proliferation and
functions; 3) Characterizing PD-L1 expression of...

## Key facts

- **NIH application ID:** 10304843
- **Project number:** 5R01CA225108-04
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** HONG DU
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $520,593
- **Award type:** 5
- **Project period:** 2018-12-04 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10304843

## Citation

> US National Institutes of Health, RePORTER application 10304843, Metabolic Regulation ofPD-L1 in CD11c+ Cells (5R01CA225108-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10304843. Licensed CC0.

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