Jason Matthews

• Bartkeviciene, Arenida; Jasukaitiene, Aldona; Zievyte, Inga; Ivanauskiene, Sandra; Stachneviciute, Gabija & Jenceviciute, Kornelija [Show all 16 contributors for this article] (2025). Baseline AHR expression shapes immune response to pharmacological modulation in PBMCs from pancreatic cancer patients. Frontiers in Immunology. 16. doi: 10.3389/fimmu.2025.1655258. Full text in Research Archive Show summary

  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.

• Olafsen, Ninni Elise; Åhrling, Samaneh Shabani; Rasmussen, Marit; Erlingsson, Linnea Anna Margaretha; Granly, Emma Nilsen & Takaoka, Akinori [Show all 7 contributors for this article] (2025). PARP7 and aryl hydrocarbon receptor differentially regulate mammary cancer cell proliferation and STING-induced type I interferon signalling. Cellular Oncology. ISSN 2211-3428. doi: 10.1007/s13402-025-01150-w. Full text in Research Archive Show summary

  Abstract Purpose PARP7 is a negative regulator of type I interferon (IFN-I) and aryl hydrocarbon receptor (AHR) signalling and has important roles in cell proliferation and antitumor immunity. Recently, several cancer cell lines have been reported to be sensitive to the antiproliferative effect of PARP7 inhibition by RBN2397; however, the roles of AHR and IFN-I signalling in this effect are not fully understood. Methods Murine mammary cancer cells were treated with AHR ligands, RBN2397 and with the stimulator of interferon genes (STING) agonist, DMXAA. The impact of ligand treatments on AHR and IFN-I signalling and cell proliferation was determined. Results RBN2397 enhanced AHR ligand signalling and STING-induced IFN-I responses in both cell lines. Py8119 but not Py230, 4T1 or EO771 cells were sensitive to the antiproliferative effects of RBN2397. In agreement with FOS-related antigen 1 (FOSL1) being required for sensitivity to RBN2397, Py8119 but not Py230 cells expressed FOSL1. However, RBN2397 insensitive 4T1 and EO771 cell lines also expressed FOSL1, suggesting that the role of FOSL1 in RBN2397-mediated growth inhibition exhibits cell line specificity. In Py8119 cells, RBN2397 induced apoptosis which was independent of AHR ligand treatment and DMXAA-induced STING activation. Although Py230 cells were resistant to the antiproliferative effects RBN2397 alone, combined treatment of DMXAA with RBN2397 reduced their proliferation, which was further reduced by AHR loss or its inhibition. Conclusion These findings highlight the complexity of the interplay among PARP7, AHR and STING-induced IFN signalling in regulating cancer cell proliferation but also suggest that for some cell lines STING activation might increase their sensitivity to the anti-proliferative effects of RBN2397.

• Stukas, Darius; Zievyte, Inga; Ivanauskiene, Sandra; Karvelyte, Gabriele; Jasukaitiene, Aldona & Bartkeviciene, Arenida [Show all 12 contributors for this article] (2025). Small-molecule inhibitor BAY synergizes with gemcitabine through AHR inhibition in pancreatic cancer cells. Biochemical Pharmacology. ISSN 0006-2952. 233. doi: 10.1016/j.bcp.2025.116798. Full text in Research Archive Show summary

  Pancreatic cancer (PC) presents a significant challenge in treatment efficacy due to late-stage diagnosis and chemoresistance. The effects of the combination of a selective small-molecule AHR inhibitor and gemcitabine treatment effectiveness in PC cells has been a focus of research. This study utilized the PC cell lines BxPC-3 and Su.86.86 to investigate the impact of AHR activity modulation on gene and protein expression related to the gemcitabine response. Assays including viability measurement, combinational index calculation, qRT–PCR, Western blot analysis, immunocytofluorescence, and clonogenic assays, were employed. Additionally, patient tissue samples were analysed for AHR, ELAVL1, and DCK levels. The results show that AHR activity modulation influenced ELAVL1 localization, DCK expression, and gemcitabine response. Inhibition of AHR activity caused synergistic effects with gemcitabine, whereas activation had an antagonistic effect. Regarding colony formation, inhibition of AHR increased gemcitabine effectiveness by 30–41%, whereas activation decreased the response by 11–28%. Patient tissue analysis revealed correlations between AHR, ELAVL1, and DCK mRNA levels and showed increased levels of AHR protein (2.2-fold) and decreased DCK protein levels (36% decrease) in tumor tissue compared to next-to-cancer tissue. These findings demonstrate the potential of AHR modulation to improve gemcitabine treatment outcomes. This study highlights the significance of AHR modulation in influencing the gemcitabine response in PC cells. By inhibiting AHR activity, cells exhibited improved gemcitabine response, offering a promising avenue for enhancing treatment efficacy. These findings suggest that AHR could serve as a target for optimizing gemcitabine treatment and potentially reducing cancer aggressiveness.

• Jeltema, Devon; Knox, Kennady; Dobbs, Nicole; Tang, Zhen; Xing, Cong & Araskiewicz, Antonina [Show all 11 contributors for this article] (2025). PARP7 inhibits type I interferon signaling to prevent autoimmunity and lung disease. Journal of Experimental Medicine (JEM). ISSN 0022-1007. 222(5). doi: 10.1084/jem.20241184. Full text in Research Archive Show summary

  Type I IFN (IFN-I) induce hundreds of antiviral genes as well as negative regulators that limit IFN-I signaling. Here, we investigate the family of 16 PARPs and find that 11 PARPs are ISGs, of which 8 PARPs inhibit IFN-I production. PARP7 is the most potent negative feedback regulator of IFN-I production. Using Parp7−/− and Parp7H532A/H532A mice, we show that PARP7 loss leads to systemic autoimmunity characterized by splenomegaly and increased autoantibodies and inflammatory cytokines. PARP7 loss also results in perivascular immune infiltration in the lung that forms tertiary lymphoid structures. Mechanistically, PARP7 inhibits multiple innate immune pathways in a cell-intrinsic and MARylation-dependent manner. PARP7 interacts with IRF3 through the catalytic domain and disrupts the IRF3:CBP/p300 transcriptional holocomplex required for IFN-I production. Irf3−/− or Irf3S1/S1 (transcription defective) or Sting−/− rescues Parp7H532A/H532A mouse autoimmunity and lung disease. Together, our study reveals physiological functions of PARP7 as a negative feedback regulator of IFN-I production that maintains immune homeostasis particularly in the lung.

• Kannen, Vinicius; Olafsen, Ninni Elise; Das, Siddhartha; Giuliana, Paolo; Izzati, Fauzia N. & Choksi, Hani [Show all 16 contributors for this article] (2025). Loss of aryl hydrocarbon receptor reduces pancreatic tumor growth by increasing immune cell infiltration. Biochemical Pharmacology. ISSN 0006-2952. 236, p. 1–12. doi: 10.1016/j.bcp.2025.116872. Full text in Research Archive
• Rundblad, Amanda; Das, Siddhartha; Ginos, Bigina N.R; Matthews, Jason; Holven, Kirsten Bjørklund & Voortman, Trudy [Show all 7 contributors for this article] (2025). Exposure to fine particulate matter in adults is associated with immune cell gene expression related to inflammation, the electron transport chain, and cell cycle regulation. Environmental Epigenetics. 11(1). doi: 10.1093/eep/dvaf008. Full text in Research Archive Show summary

  Exposure to air pollution and an unhealthy built environment increase disease risk by impacting metabolic risk factors and inflammation, potentially via epigenetic modifications and effects on gene expression. We aimed to explore associations between fine particulate matter (PM2.5), black carbon, ozone, nitrogen dioxide, distance to nearest water body, normalized difference vegetation index, and impervious surface and gene expression profiles in adults. This study is a part of the LongITools project and includes cross-sectional data from the Rotterdam Study, a population-based cohort study, and NoMa, a randomized controlled trial. Environmental exposures were assigned using land-use regression (LUR) models and satellite data. Gene expression was assessed with whole blood RNA sequencing (Rotterdam Study, n = 758) and microarray analyses in peripheral blood mononuclear cells (NoMa, n = 100). We analysed transcriptomic profiles and enriched pathways associated with each of the environmental exposures. PM2.5 had the strongest gene expression associations, while only a few significant associations were observed for the other environmental exposures. In both populations, exposure to PM2.5 was associated with genes and pathways related to inflammation, oxidative stress, DNA metabolism, cell cycle regulation, histones, electron transport chain, oxidative phosphorylation, and neural signalling. This study is limited by different methods for RNA quantification, a cross-sectional design, and a small sample size. However, in both populations, exposure to PM2.5 resulted in the maximum number of associations with gene expression. In conclusion, PM2.5 is strongly associated with various gene expression profiles, which provide information about the underlying mechanisms of the detrimental health effects of exposure to PM2.5.

• Kannen, Vinicius; Rasmussen, Marit; Das, Siddhartha; Giuliana, Paolo; Izzati, Fauzia N. & Choksi, Hani [Show all 18 contributors for this article] (2025). Loss of Parp7 increases type I interferon signalling and reduces pancreatic tumour growth by enhancing immune cell infiltration. Frontiers in Immunology. 15. doi: 10.3389/fimmu.2024.1513595. Full text in Research Archive Show summary

  Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal forms of cancer, and despite low incidence rates, it remains the sixth leading cause of cancer related deaths worldwide. Immunotherapy, which aims to enhance the immune system’s ability to recognize and eliminate cancer cells, has emerged as a promising approach in the battle against PDAC. PARP7, a mono-ADP-ribosyltransferase, is a negative regulator of the type I interferon (IFN-I) pathway and has been reported to reduce anti-tumour immunity.Methods: We used murine pancreatic cancer cells, CR705, CRISPR/Cas9, in vivo tumour models and spectral flow cytometry to determine the role of PARP7 in pancreatic tumour growth.Results: Loss of Parp7 elevated the levels of interferon stimulated gene factor 3 (ISGF3) and its downstream target genes, even in the absence of STING. Cancer cells knocked out for Parp7 (CR705Parp7KO) produced smaller tumours than control cells (CR705Cas9) when injected into immunocompetent mice. Transcriptomic analyses revealed that CR705Parp7KO tumours had increased expression of genes involved in immunoregulatory interactions and interferon signalling pathways. Characterization of tumour infiltrating leukocyte (TIL) populations showed that CR705Parp7KO tumours had higher proportions of natural killer cells, CD8+ T cells and a lower proportion of anti-inflammatory macrophages (M2). The overall TIL profile of CR705Parp7KO tumours was suggestive of a less suppressive microenvironment.Conclusions: Our data show that loss of Parp7 reduces PDAC tumour growth by increasing the infiltration of immune cells and enhancing anti-tumour immunity. These findings provide support to pursue PARP7 as a therapeutic target for cancer treatment.

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• Granly, Emma Nilsen; Åhrling, Samaneh Shabani; Alvik, Karoline; Das, Siddhartha & Matthews, Jason (2025). Aryl Hydrocarbon Receptor Differentially Regulated Gene Expression Profiles in Resting and Polarized Bone Marrow-Derived Macrophages. Full text in Research Archive
• Åhrling, Samaneh Shabani; Das, Siddhartha; Olafsen, Ninni Elise; Granly, Emma Nilsen & Matthews, Jason (2025). Differential Effects of Loss and Pharmacological Inhibition of Aryl Hydrocarbon Receptor on Mammary Tumor Growth. Full text in Research Archive
• Zegeye, Fikirte Debebe; Samulin-Erdem, Johanna Maria; Straumfors, Anne & Matthews, Jason (2026). Occupational exposure and associated health effects among workers in the shrimp processing industry. Universitetet i Oslo. ISSN 9788234807909. Full text in Research Archive Show summary

  Respiratory ailments, such as cough, breathlessness, asthma and allergy, are prevalent among workers in the seafood industry. These health problems have largely been attributed to exposure to allergenic proteins, yet the contributions of other components in the work environment remain insufficiently understood. The aim of this thesis was to investigate the relationship between occupational exposure to allergenic proteins and microbial agents in shrimp processing environments and respiratory health outcomes, including symptoms, allergic sensitisation, and inflammatory responses. Respiratory symptoms as well as allergy and asthma-related biomarkers were assessed among Norwegian shrimp processing workers using questionnaires and blood analyses. Occupational exposure was characterised through work-environment air sampling, protein measurements, microbial identification, and proteomic analyses. Shrimp processing workers reported a higher prevalence of upper and chronic lower respiratory symptoms than controls and exhibited elevated levels of inflammatory, allergy and asthma-related biomarkers. Multiple known and potential shrimp allergens were identified in workplace air, with particularly high levels of tropomyosin detected during shrimp cooking. Airborne microbial exposure was further characterised across different shrimp processing tasks using full-shift personal air sampling and molecular analyses. Higher bacterial load, species richness, and immune activation potential were observed during work processes involving raw shrimp, while cooking substantially reduced bacterial exposure. Experimental studies using human alveolar co-culture cell models demonstrated that combined exposure to shrimp allergens and microbial components can enhance inflammatory responses relative to individual exposures. Overall, the findings demonstrate that complex occupational bioaerosol exposure contributes to respiratory health risks among shrimp-processing workers, with task-specific exposure differences underscoring the need for targeted preventive measures.

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