PPARγ induces PD-L1 expression in MSS+ colorectal cancer cells

Oncoimmunology. 2021 May 5;10(1):1906500. doi: 10.1080/2162402X.2021.1906500.

Abstract

Only a small subset of colorectal cancer (CRC) patients benefits from immunotherapies, comprising blocking antibodies (Abs) against checkpoint receptor "programmed-cell-death-1" (PD1) and its ligand (PD-L1), because most cases lack the required mutational burden and neo-antigen load caused by microsatellite instability (MSI) and/or an inflamed, immune cell-infiltrated PD-L1+ tumor microenvironment. Peroxisome proliferator-activated-receptor-gamma (PPARγ), a metabolic transcription factor stimulated by anti-diabetic drugs, has been previously implicated in pre/clinical responses to immunotherapy. We therefore raised the hypothesis that PPARγ induces PD-L1 on microsatellite stable (MSS) tumor cells to enhance Ab-target engagement and responsiveness to PD-L1 blockage. We found that PPARγ-agonists upregulate PD-L1 mRNA/protein expression in human gastrointestinal cancer cell lines and MSS+ patient-derived tumor organoids (PDOs). Mechanistically, PPARγ bound to and activated DNA-motifs similar to cognate PPARγ-responsive-elements (PPREs) in the proximal -2 kb promoter of the human PD-L1 gene. PPARγ-agonist reduced proliferation and viability of tumor cells in co-cultures with PD-L1 blocking Ab and lymphokine-activated killer cells (LAK) derived from the peripheral blood of CRC patients or healthy donors. Thus, metabolic modifiers improved the antitumoral response of immune checkpoint Ab, proposing novel therapeutic strategies for CRC.

Keywords: Immunotherapy; MSS; PD-L1; PPAR; cancer; colorectal.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • B7-H1 Antigen / genetics
  • Colorectal Neoplasms* / drug therapy
  • Humans
  • Microsatellite Instability
  • PPAR gamma* / genetics
  • Tumor Microenvironment

Substances

  • B7-H1 Antigen
  • PPAR gamma

Grants and funding

EB received funding from German Cancer Aid (Deutsche Krebshilfe 108287, 111086), German Research Foundation (Deutsche Forschungsgemeinschaft DFG, Bu2285) and German Cancer Research Center (Deutsches Krebsforschungszentrum DKFZ-MOST, Ca158). LH, JR, TS and VH were supported by MD fellowships; JB, MEc, PW and TGu by the “Translational Physician Scientist” (TraPS) program; WW by the “Translational Medical Research” (TMR) master program (all from the Medical Faculty Mannheim, University Heidelberg); TZ by the Clinician Scientist program “Interfaces and Interventions in complex chronic conditions” (ICON) of the DFG. BL received an MD fellowship from the Chinese Scholarship Council (CSC). ID held funding from the MD/PhD Masterprogram (University of Strasbourg and Universite Descartes Paris). AC, MB and ME were supported by a grant provided by the MERCK Heidelberg Innovation Call (Darmstadt, Germany). AC received funding from DFG [SFB1366 (394046768-SFB1366; C2 to AC); TRR179 (TP07 to AC); SFB-TRR156 (B10N to AC); RTG2099 (259332240-RTG2099; P9 to AC)], Baden-Württemberg Foundation special program “Angioformatics Single Cell Platform” and a network grant of the European Commission (H2020-MSCA-MC-ITN-765104-NATURE-NK)