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A Human Peripheral Blood Mononuclear Cell PBMC Engrafted Humanized Xenograft Model for Translational Immuno-oncology I-O Research
Published on: August 15, 2019
Baseline AHR expression shapes immune response to pharmacological modulation in PBMCs from pancreatic cancer patients
Arenida Bartkeviciene1, Aldona Jasukaitiene1, Inga Zievyte1
1Laboratory of Surgical Gastroenterology, Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania.
Background:
Pancreatic ductal adenocarcinoma (PDAC) remains largely unresponsive to immunotherapy because of its highly immunosuppressive tumor microenvironment. Aryl hydrocarbon receptor (AHR), a ligand-dependent transcription factor, has emerged as a key regulator of immune homeostasis and inflammation. However, its systemic immunomodulatory role in PDAC, particularly outside the tumor microenvironment, remains poorly understood.
Methods:
Peripheral blood mononuclear cells (PBMCs) from patients with PDAC and healthy donors were isolated and treated ex vivo with two AHR agonists (Carbidopa and Tapinarof) and one antagonist (BAY 2416964). The samples were stratified into Low and High/Medium AHR expression groups. Flow cytometry (FC), qPCR, ELISA, Luminex assays, and immunofluorescence imaging were used to evaluate immune checkpoint expression, cytokine secretion, monocyte polarization, and subcellular AHR localization. Overall survival analysis was performed based on the baseline AHR expression levels.
Results:
Baseline AHR expression strongly influenced the immunological effects of AHR modulators. In High/Medium AHR PBMCs, Carbidopa increased PD-L1 and soluble PD-1 (sPD-1) levels, while IL10 expression was suppressed. In contrast, BAY significantly reduced PD-1 and sPD-1 levels in Low AHR PBMCs, whereas Tapinarof induced the highest IL10 expression. All modulators reduced the proportion of M2-like monocytes, indicating a shift toward less immunosuppressive phenotypes. Nuclear translocation of AHR protein varied across treatments and expression levels. Kaplan-Meier analysis revealed a non-significant trend toward improved overall survival in the High/Medium AHR group (log-rank p = 0.276).
Conclusion:
Baseline AHR expression critically shapes the immune response to pharmacological modulation in PBMCs from PDAC patients. These findings suggest that AHR profiling may serve as a clinically relevant biomarker for stratifying patients and guiding personalized immunotherapy approaches for PDAC.
Insights
Aryl hydrocarbon receptor (AHR) expression in pancreatic cancer patients influences immunotherapy response. Modulating AHR in peripheral blood cells impacts immune cells and suggests AHR profiling for personalized treatment strategies.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- Pancreatic ductal adenocarcinoma (PDAC) is resistant to immunotherapy due to an immunosuppressive tumor microenvironment.
- Aryl hydrocarbon receptor (AHR) regulates immune homeostasis, but its role in PDAC immunity is unclear.
Purpose of the Study:
- To investigate the systemic immunomodulatory role of AHR in PDAC.
- To evaluate the effects of AHR modulators on immune cells from PDAC patients.
Main Methods:
- Peripheral blood mononuclear cells (PBMCs) from PDAC patients and healthy donors were treated ex vivo with AHR agonists/antagonist.
- Immune checkpoint expression, cytokine secretion, and monocyte polarization were analyzed using flow cytometry, qPCR, ELISA, and Luminex.
- Overall survival was assessed based on baseline AHR expression.
Main Results:
- Baseline AHR expression modulated the immune response to AHR modulators.
- Specific AHR modulators differentially affected PD-L1, sPD-1, and IL10 levels.
- All modulators shifted monocytes towards less immunosuppressive phenotypes.
Conclusions:
- Baseline AHR levels critically shape immune responses to pharmacological modulation in PDAC.
- AHR profiling may serve as a biomarker for patient stratification and personalized immunotherapy in PDAC.
