PPARγ activation sensitizes MSS gastrointestinal cancer cells to PD1 blockage
Juliane Reichling1, Beifang Li2, Yanxiong Yu1
1Dept. of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
Objectives:
Antibodies (Abs) against immune checkpoint "programmed-cell-death-1" (PD1) achieve benefit in patients with microsatellite instable (MSI), immunologically "hot" gastrointestinal (GI) cancers, but fail in cases with "cold" microsatellite stable (MSS) tumors. One underlying mechanism of therapy failure are activating KRAS mutations which up-regulate PD1 within an immunosuppressive microenvironment. Peroxisome-proliferator-activated-receptor-gamma (PPARγ) is a drugable anti-diabetic and immune-regulatory transcription factor which inhibits RAS signaling. We therefore assessed if PPARγ attenuates PD1 expression and/or function on immune cells and augments efficacy of PD1-blockage.
Methods:
Tissue samples of patients with colorectal and gastric cancers, wildtype (WT) and KRASG12V transgenic C57BL6/J mice on a 3-months diet enriched with PPARγ-agonist (rosiglitazone, rosi, ∼25 mg/kg*day) were analysed by PCR and immunohistochemistry. Cocultures of human MSS GI cancer cell lines (AGS, HT29, SW480) with "lymphokine-activated NK/T killer cells" (LAK) from peripheral blood of healthy donors were subjected to PCR microarray, immunoblot, flow cytometry and viability assays.
Results:
KRASG12V mouse intestinal tissues had more PD1 than WT littermates, and PD1 was co-expressed with PPARγ in human GI cancers. Combination of rosi and interferon-gamma (IFNγ) reduced the viability of human KRAS/BRAF mutant MSS tumor cells in presence of LAK and PD1 blocking Ab (pembrolizumab). Mechanistically, PD1 protein was down-regulated and tyrosine phosphorylation of PP60 and signal-transducer-and-activator-of-transcription-1 (STAT1) enhanced in LAK. MHCclassI and PD1-ligand (PDL1) were up-regulated on cocultured tumor cells, endowing them with higher immunogenicity.
Conclusion:
Pharmacological activation of PPARγ enhanced anti-tumor efficacy of PD1-blockage. Thus, metabolic modifiers might be developed as immunosensitizers for clinical checkpoint therapies against MSS tumors.
Insights
Activating peroxisome-proliferator-activated-receptor-gamma (PPARγ) with rosiglitazone enhanced anti-tumor effects of programmed-cell-death-1 (PD1) blockade in microsatellite stable gastrointestinal cancers. This suggests metabolic modifiers can sensitize cold tumors to checkpoint immunotherapies.
Area of Science:
- Oncology
- Immunology
- Metabolic pathways
Background:
- Programmed-cell-death-1 (PD1) antibodies benefit microsatellite instable (MSI) cancers but fail in microsatellite stable (MSS) tumors.
- Activating KRAS mutations promote PD1 expression in an immunosuppressive tumor microenvironment.
- Peroxisome-proliferator-activated-receptor-gamma (PPARγ) inhibits RAS signaling and has immune-regulatory functions.
Purpose of the Study:
- To investigate if PPARγ activation can reduce PD1 expression and/or function on immune cells.
- To determine if PPARγ activation can enhance the efficacy of PD1 blockade therapy.
Main Methods:
- Analysis of colorectal and gastric cancer tissues from patients and KRASG12V transgenic mice.
- Treatment of mice with a PPARγ agonist (rosiglitazone).
- Coculture assays using human MSS GI cancer cell lines and lymphokine-activated NK/T killer cells (LAK), followed by molecular and cellular analyses.
Main Results:
- KRASG12V tissues showed increased PD1 expression compared to wild-type.
- Rosiglitazone combined with interferon-gamma reduced viability of KRAS/BRAF mutant MSS tumor cells when treated with PD1 blocking antibodies.
- PPARγ activation led to decreased PD1 protein in LAK cells and increased tumor cell immunogenicity via upregulation of MHC Class I and PDL1.
Conclusions:
- Pharmacological activation of PPARγ enhances the anti-tumor efficacy of PD1 blockade.
- Metabolic modifiers could serve as immunosensitizers for clinical checkpoint therapies targeting MSS tumors.
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