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 CD11c+ cells in tumor stimulation. The successful outcome will help to design a more efficient regimen to increase the efficacy of PD-L1 cancer immunotherapy by manipulating the metabolic pathway and the immune checkpoint pathway.

Public Health Relevance

The successful outcomes of this pre-clinical application will elucidate a molecular mechanism for how highly expressed PD-L1 converts CD11c+ cells from immune stimulation to immune suppression and promote tumor growth, and identify a target to intervene the inflammatory tumor environment in cancer treatment.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA225108-01A1
Application #
9666554
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Howcroft, Thomas K
Project Start
2018-12-04
Project End
2023-11-30
Budget Start
2018-12-04
Budget End
2019-11-30
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Pathology
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202