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Principal Investigator: Tyler J. Curiel
Organization: GEORGE WASHINGTON UNIVERSITY
Fiscal Year: 2024
Award: $675,405
Funding agency: National Cancer Institute
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.
Terms: <Ablation><Adipocytes><Adipose Cell><Adipose tissue><Affect><Antibodies><B7-H1><B7H1><Binding><Biology><Breast><Breast Cancer><Breast Cancer Patient><Breast Cancer therapy><Breast Neoplasms><Breast Tissue><Breast Tumor Patient><Breast Tumors><CD274><Cancer Biology><Cancer Burden><Cancer Patient><Cancers><Cell Body><Cell Communication><Cell Communication and Signaling><Cell Interaction><Cell Signaling><Cell-to-Cell Interaction><Cells><Chronic><Clinical Trials><Co-culture><Cocultivation><Coculture><Coculture Techniques><Complex><Data><Development><Exclusion><Fat Cells><Fatty Tissue><Foundations><Gene Action Regulation><Gene Expression Regulation><Gene Regulation><Gene Regulation Process><Gene Transcription><Genetic Transcription><Health><Immune><Immune mediated therapy><Immunes><Immunologically Directed Therapy><Immunomodulation><Immunotherapy><In Vitro><Inflammation><Intracellular Communication and Signaling><KO mice><Knock-out Mice><Knockout Mice><Leanness><Link><Lipocytes><Lymphatic cell><Lymphocyte><Lymphocytic><Malignant Breast Neoplasm><Malignant Neoplasms><Malignant Tumor><Mammary Cancer><Mammary Gland Parenchyma><Mammary Gland Tissue><Mammary Neoplasms><Mature Lipocyte><Mature fat cell><Mediating><Metabolic dysfunction><Modeling><Molecular><Molecular Interaction><National Cancer Burden><Non obese><Nonobese><Null Mouse><Obesity><Oncogenesis><PD 1><PD-1><PD-L1><PD1><PDL-1><PDL1><Pathway interactions><Patients><Position><Positioning Attribute><Prediction of Response to Therapy><Programmed Cell Death 1 Ligand 1><Programmed Death Ligand 1><Proteins><RNA Expression><Receptor Protein><Role><Shapes><Signal Transduction><Signal Transduction Systems><Signaling><Solid><Solid Neoplasm><Solid Tumor><Source><Stromal Cells><System><Testing><Therapeutic><Thinness><Transcription><Transcription Regulation><Transcriptional Control><Transcriptional Regulation><Tumor Cell><Tumor Immunity><Tumor Promotion><Tumor-infiltrating immune cells><Up-Regulation><Upregulation><Work><aPD-1><aPD-L1><aPD1><aPDL1><adipogenesis><adipose><adiposity><anti programmed cell death 1><anti programmed cell death ligand 1><anti programmed cell death protein ligand 1><anti-PD-(L)1><anti-PD-1><anti-PD-L1><anti-PD1><anti-PDL-1><anti-PDL1><anti-cancer immunotherapy><anti-programmed cell death protein 1><anti-tumor immunity><antiPD-1><antiPD-L1><antiPD1><antiPDL1><anticancer immunotherapy><antitumor immunity><attenuation><behavior influence><behavioral influence><biological signal transduction><cancer immunity><cancer immunology><cancer immunotherapy><cancer microenvironment><cancer progression><cancer type><cell type><check point blockade><check point immunotherapy><check point inhibitor therapy><check point inhibitory therapy><check point therapy><checkpoint blockade><checkpoint immunotherapy><checkpoint inhibitor therapy><checkpoint inhibitory therapy><checkpoint therapy><clinical relevance><clinically relevant><corpulence><developmental><experiment><experimental research><experimental study><experiments><fat metabolism><genomic tools><immune cell infiltration of tumors><immune cells infiltrating the tumor><immune cells that infiltrate the tumor><immune check point><immune check point blockade><immune check point therapy><immune checkpoint><immune checkpoint blockade><immune checkpoint therapy><immune modulation><immune regulation><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based cancer therapies><immune-based therapies><immune-based treatments><immunecheckpoint><immuno therapy><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><immunotherapy for cancer><immunotherapy of cancer><improved><infiltration of tumors by immune cells><insight><intratumoral immune cell><intratumoral immune infiltrate><lipid biosynthesis><lipid metabolism><lipogenesis><lymph cell><malignancy><malignant breast tumor><mammary tumor><mortality><mouse model><murine model><neoplasm immunology><neoplasm progression><neoplasm/cancer><neoplastic cell><neoplastic progression><new approaches><novel><novel approaches><novel strategies><novel strategy><pathway><predict therapeutic response><predict therapy response><predictive tools><programmed cell death 1><programmed cell death ligand 1><programmed cell death protein 1><programmed cell death protein ligand 1><programmed death 1><programs><protein death-ligand 1><receptor><response><response to therapy><response to treatment><sle2><social role><systemic lupus erythematosus susceptibility 2><therapeutic response><therapy prediction><therapy response><tool><treatment prediction><treatment response><treatment response prediction><treatment responsiveness><tumor><tumor growth><tumor immune cell><tumor immune infiltrate><tumor immunology><tumor infiltration of immune cells><tumor microenvironment><tumor progression><tumorigenesis><white adipose tissue><yellow adipose tissue><αPD-1><αPD-L1><αPD1><αPDL1>