Publications by authors named "Jonas Van Audenaerde"

11 Publications

  • Page 1 of 1

Macrophage miR-210 induction and metabolic reprogramming in response to pathogen interaction boost life-threatening inflammation.

Sci Adv 2021 May 7;7(19). Epub 2021 May 7.

Laboratory of Tumor Inflammation and Angiogenesis, CCB, VIB, Leuven, Belgium.

Unbalanced immune responses to pathogens can be life-threatening although the underlying regulatory mechanisms remain unknown. Here, we show a hypoxia-inducible factor 1α-dependent microRNA (miR)-210 up-regulation in monocytes and macrophages upon pathogen interaction. MiR-210 knockout in the hematopoietic lineage or in monocytes/macrophages mitigated the symptoms of endotoxemia, bacteremia, sepsis, and parasitosis, limiting the cytokine storm, organ damage/dysfunction, pathogen spreading, and lethality. Similarly, pharmacologic miR-210 inhibition improved the survival of septic mice. Mechanistically, miR-210 induction in activated macrophages supported a switch toward a proinflammatory state by lessening mitochondria respiration in favor of glycolysis, partly achieved by downmodulating the iron-sulfur cluster assembly enzyme ISCU. In humans, augmented miR-210 levels in circulating monocytes correlated with the incidence of sepsis, while serum levels of monocyte/macrophage-derived miR-210 were associated with sepsis mortality. Together, our data identify miR-210 as a fine-tuning regulator of macrophage metabolism and inflammatory responses, suggesting miR-210-based therapeutic and diagnostic strategies.
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http://dx.doi.org/10.1126/sciadv.abf0466DOI Listing
May 2021

Cancer-Associated Fibroblasts as a Common Orchestrator of Therapy Resistance in Lung and Pancreatic Cancer.

Cancers (Basel) 2021 Feb 27;13(5). Epub 2021 Feb 27.

Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), University of Antwerp, B2610 Antwerp, Belgium.

Cancer arises from mutations accruing within cancer cells, but the tumor microenvironment (TME) is believed to be a major, often neglected, factor involved in therapy resistance and disease progression. Cancer-associated fibroblasts (CAFs) are prominent and key components of the TME in most types of solid tumors. Extensive research over the past decade revealed their ability to modulate cancer metastasis, angiogenesis, tumor mechanics, immunosuppression, and drug access through synthesis and remodeling of the extracellular matrix and production of growth factors. Thus, they are considered to impede the response to current clinical cancer therapies. Therefore, targeting CAFs to counteract these protumorigenic effects, and overcome the resistance to current therapeutic options, is an appealing and emerging strategy. In this review, we discuss how CAFs affect prognosis and response to clinical therapy and provide an overview of novel therapies involving CAF-targeting agents in lung and pancreatic cancer.
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http://dx.doi.org/10.3390/cancers13050987DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7956441PMC
February 2021

The Search for an Interesting Partner to Combine with PD-L1 Blockade in Mesothelioma: Focus on TIM-3 and LAG-3.

Cancers (Basel) 2021 Jan 14;13(2). Epub 2021 Jan 14.

Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), University of Antwerp, 2610 Wilrijk, Belgium.

Malignant pleural mesothelioma (MPM) is an aggressive cancer that is causally associated with previous asbestos exposure in most afflicted patients. The prognosis of patients remains dismal, with a median overall survival of only 9-12 months, due to the limited effectiveness of any conventional anti-cancer treatment. New therapeutic strategies are needed to complement the limited armamentarium against MPM. We decided to focus on the combination of different immune checkpoint (IC) blocking antibodies (Abs). Programmed death-1 (PD-1), programmed death ligand-1 (PD-L1), T-cell immunoglobulin mucin-3 (TIM-3), and lymphocyte activation gene-3 (LAG-3) blocking Abs were tested as monotherapies, and as part of a combination strategy with a second IC inhibitor. We investigated their effect in vitro by examining the changes in the immune-related cytokine secretion profile of supernatant collected from treated allogeneic MPM-peripheral blood mononuclear cell (PBMC) co-cultures. Based on our in vitro results of cytokine secretion, and flow cytometry data that showed a significant upregulation of PD-L1 on PBMC after co-culture, we chose to further investigate the combinations of anti PD-L1 + anti TIM-3 versus anti PD-L1 + anti LAG-3 therapies in vivo in the AB1-HA BALB/cJ mesothelioma mouse model. PD-L1 monotherapy, as well as its combination with LAG-3 blockade, resulted in in-vivo delayed tumor growth and significant survival benefit.
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http://dx.doi.org/10.3390/cancers13020282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7838786PMC
January 2021

Novel combination immunotherapy for pancreatic cancer: potent anti-tumor effects with CD40 agonist and interleukin-15 treatment.

Clin Transl Immunology 2020 15;9(8):e1165. Epub 2020 Aug 15.

Center for Oncological Research (CORE) Integrated Personalized & Precision Oncology Network (IPPON) University of Antwerp Wilrijk Belgium.

Objectives: With the poorest 5-year survival of all cancers, improving treatment for pancreatic cancer is one of the biggest challenges in cancer research. We sought to explore the potential of combining both priming and activation of the immune system. To achieve this, we combined a CD40 agonist with interleukin-15 and tested its potential in pancreatic cancer.

Methods: Response to this combination regimen was assessed in pancreatic ductal adenocarcinoma mouse models, and a thorough analysis of the tumor microenvironment was performed.

Results: We demonstrated profound reduction in tumor growth and increased survival of mice with the majority of mice being cured when both agents were combined, including an unprecedented 8-fold dose reduction of CD40 agonist without losing any efficacy. RNAseq analysis showed involvement of natural killer (NK) cell- and T-cell-mediated anti-tumor responses and the importance of antigen-presenting cell pathways. This combination resulted in enhanced infiltration of tumors by both T cells and NK cells, as well as a striking increase in the ratio of CD8 T cells over Tregs. We also observed a significant increase in numbers of dendritic cells (DCs) in tumor-draining lymph nodes, particularly CD103 DCs with cross-presentation potential. A critical role for CD8 T cells and involvement of NK cells in the anti-tumor effect was highlighted. Importantly, strong immune memory was established, with an increase in memory CD8 T cells only when both interleukin-15 and the CD40 agonist were combined.

Conclusion: These novel preclinical data support initiation of a first-in-human clinical trial with this combination immunotherapy strategy in pancreatic cancer.
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http://dx.doi.org/10.1002/cti2.1165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7428816PMC
August 2020

Clinically Relevant Chemotherapeutics Have the Ability to Induce Immunogenic Cell Death in Non-Small Cell Lung Cancer.

Cells 2020 06 16;9(6). Epub 2020 Jun 16.

Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), 2610 Wilrijk, Belgium.

The concept of immunogenic cell death (ICD) has emerged as a cornerstone of therapy-induced anti-tumor immunity. To this end, the following chemotherapies were evaluated for their ability to induce ICD in non-small cell lung cancer (NSCLC) cell lines: docetaxel, carboplatin, cisplatin, oxaliplatin and mafosfamide. The ICD hallmarks ATP, ecto-calreticulin, HMGB1, phagocytosis and maturation status of dendritic cells (DCs) were assessed in vitro. Furthermore, an in vivo vaccination assay on C57BL/6J mice was performed to validate our in vitro results. Docetaxel and the combination of docetaxel with carboplatin or cisplatin demonstrated the highest levels of ATP, ecto-calreticulin and HMGB1 in three out of four NSCLC cell lines. In addition, these regimens resulted in phagocytosis of treated NSCLC cells and maturation of DCs. Along similar lines, all mice vaccinated with NSCLC cells treated with docetaxel and cisplatin remained tumor-free after challenge. However, this was not the case for docetaxel, despite its induction of the ICD-related molecules in vitro, as it failed to reject tumor growth at the challenge site in 60% of the mice. Moreover, our in vitro and in vivo data show the inability of oxaliplatin to induce ICD in NSCLC cells. Overall with this study we demonstrate that clinically relevant chemotherapeutic regimens in NSCLC patients have the ability to induce ICD.
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http://dx.doi.org/10.3390/cells9061474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7349161PMC
June 2020

Cold Atmospheric Plasma-Treated PBS Eliminates Immunosuppressive Pancreatic Stellate Cells and Induces Immunogenic Cell Death of Pancreatic Cancer Cells.

Cancers (Basel) 2019 Oct 19;11(10). Epub 2019 Oct 19.

Center for Oncological Research, University of Antwerp, 2610 Wilrijk, Belgium.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers with a low response to treatment and a five-year survival rate below 5%. The ineffectiveness of treatment is partly because of an immunosuppressive tumor microenvironment, which comprises tumor-supportive pancreatic stellate cells (PSCs). Therefore, new therapeutic strategies are needed to tackle both the immunosuppressive PSC and pancreatic cancer cells (PCCs). Recently, physical cold atmospheric plasma consisting of reactive oxygen and nitrogen species has emerged as a novel treatment option for cancer. In this study, we investigated the cytotoxicity of plasma-treated phosphate-buffered saline (pPBS) using three PSC lines and four PCC lines and examined the immunogenicity of the induced cell death. We observed a decrease in the viability of PSC and PCC after pPBS treatment, with a higher efficacy in the latter. Two PCC lines expressed and released damage-associated molecular patterns characteristic of the induction of immunogenic cell death (ICD). In addition, pPBS-treated PCC were highly phagocytosed by dendritic cells (DCs), resulting in the maturation of DC. This indicates the high potential of pPBS to trigger ICD. In contrast, pPBS induced no ICD in PSC. In general, pPBS treatment of PCCs and PSCs created a more immunostimulatory secretion profile (higher TNF-α and IFN-γ, lower TGF-β) in coculture with DC. Altogether, these data show that plasma treatment via pPBS has the potential to induce ICD in PCCs and to reduce the immunosuppressive tumor microenvironment created by PSCs. Therefore, these data provide a strong experimental basis for further in vivo validation, which might potentially open the way for more successful combination strategies with immunotherapy for PDAC.
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http://dx.doi.org/10.3390/cancers11101597DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6826654PMC
October 2019

Natural killer cells and their therapeutic role in pancreatic cancer: A systematic review.

Pharmacol Ther 2018 09 13;189:31-44. Epub 2018 Apr 13.

Center for Oncological Research, University of Antwerp, Antwerp, Belgium; Center for Cell Therapy and Regenerative Medicine, Antwerp University Hospital, Antwerp, Belgium.

Pancreatic cancer is among the three deadliest cancers worldwide with the lowest 5-year survival of all cancers. Despite all efforts, therapeutic improvements have barely been made over the last decade. Even recent highly promising targeted and immunotherapeutic approaches did not live up to their expectations. Therefore, other horizons have to be explored. Natural Killer (NK) cells are gaining more and more interest as a highly attractive target for cancer immunotherapies, both as pharmaceutical target and for cell therapies. In this systematic review we summarise the pathophysiological adaptions of NK cells in pancreatic cancer and highlight possible (future) therapeutic NK cell-related targets. Furthermore, an extensive overview of recent therapeutic approaches with an effect on NK cells is given, including cytokine-based, viro- and bacteriotherapy and cell therapy. We also discuss ongoing clinical trials that might influence NK cells. In conclusion, although several issues regarding NK cells in pancreatic cancer remain unsolved and need further investigation, extensive evidence is already provided that support NK cell oriented approaches in pancreatic cancer.
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http://dx.doi.org/10.1016/j.pharmthera.2018.04.003DOI Listing
September 2018

Poly(I:C) primes primary human glioblastoma cells for an immune response invigorated by PD-L1 blockade.

Oncoimmunology 2018;7(3):e1407899. Epub 2017 Dec 12.

Center for Oncological Research, University of Antwerp, Wilrijk, Antwerp, Belgium.

Prognosis of glioblastoma remains dismal, underscoring the need for novel therapies. Immunotherapy is generating promising results, but requires combination strategies to unlock its full potential. We investigated the immunomodulatory capacities of poly(I:C) on primary human glioblastoma cells and its combinatorial potential with programmed death ligand (PD-L) blockade. In our experiments, poly(I:C) stimulated expression of both PD-L1 and PD-L2 on glioblastoma cells, and a pro-inflammatory secretome, including type I interferons (IFN) and chemokines CXCL9, CXCL10, CCL4 and CCL5. IFN-β was partially responsible for the elevated PD-1 ligand expression on these cells. Moreover, real-time PCR and chloroquine-mediated blocking experiments indicated that poly(I:C) triggered Toll-like receptor 3 to elicit its effect. Cocultures of poly(I:C)-treated glioblastoma cells with peripheral blood mononuclear cells enhanced lymphocytic activation (CD69, IFN-γ) and cytotoxic capacity (CD107a, granzyme B). Additional PD-L1 blockade further propagated immune activation. Besides activating immunity, poly(I:C)-treated glioblastoma cells also doubled the attraction of CD8 T cells, and to a lesser extent CD4 T cells, via a mechanism which included CXCR3 and CCR5 ligands. Our results indicate that by triggering glioblastoma cells, poly(I:C) primes the tumor microenvironment for an immune response. Secreted cytokines allow for immune activation while chemokines attract CD8 T cells to the front, which are postulated as a prerequisite for effective PD-1/PD-L1 blockade. Accordingly, additional blockade of the concurrently elevated tumoral PD-L1 further reinforces the immune activation. In conclusion, our data proposes poly(I:C) treatment combined with PD-L1 blockade to invigorate the immune checkpoint inhibition response in glioblastoma.
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http://dx.doi.org/10.1080/2162402X.2017.1407899DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5790389PMC
December 2017

Abundant expression of TIM-3, LAG-3, PD-1 and PD-L1 as immunotherapy checkpoint targets in effusions of mesothelioma patients.

Oncotarget 2017 Oct 21;8(52):89722-89735. Epub 2017 Sep 21.

Center for Oncological Research, University of Antwerp, Antwerp, Belgium.

Malignant pleural mesothelioma (MPM) is an aggressive cancer with an increasing incidence, poor prognosis and limited effective treatment options. Hence, new treatment strategies are warranted which include immune checkpoint blockade approaches with encouraging preliminary data. Research on the immunological aspects of the easily accessible mesothelioma microenvironment could identify prognostic and/or predictive biomarkers and provide useful insights for developing effective immunotherapy. In this context, we investigated the immune cell composition of effusions (pleural and ascites fluids) from 11 different chemotherapy-treated MPM patients. We used multicolor flow cytometry to describe different subsets of immune cells and their expression of immune checkpoint molecules TIM-3, LAG-3, PD-1 and PD-L1. We demonstrate a patient-dependent inter- and intraspecific variation comparing pleural and ascites fluids in immune cell composition and immune checkpoint expression. We found CD4 and CD8 T cells, B cells, macrophages, natural killer cells, dendritic cells and tumor cells in the fluids. To the best of our knowledge, we are the first to report TIM-3 and LAG-3 expression and we confirm PD-1 and PD-L1 expression on different MPM effusion-resident immune cells. Moreover, we identified two MPM effusion-related factors with clinical value: CD4+ T cells were significantly correlated with better response to chemotherapy, while the percentage of PD-L1 podoplanin (PDPN) tumor cells is a significant prognostic factor for worse outcome. Our data provide a basis for more elaborate research on MPM effusion material in the context of treatment follow-up and prognostic biomarkers and the development of immune checkpoint-targeted immunotherapy.
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http://dx.doi.org/10.18632/oncotarget.21113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5685704PMC
October 2017

Interleukin-15 stimulates natural killer cell-mediated killing of both human pancreatic cancer and stellate cells.

Oncotarget 2017 Aug 25;8(34):56968-56979. Epub 2017 May 25.

Center for Oncological Research, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.

Pancreatic ductal adenocarcinoma (PDAC) is the 4 leading cause of cancer-related death in Western countries with a 5-year survival rate below 5%. One of the hallmarks of this cancer is the strong desmoplastic reaction within the tumor microenvironment (TME), orchestrated by activated pancreatic stellate cells (PSC). This results in a functional and mechanical shield which causes resistance to conventional therapies. Aiming to overcome this resistance by tackling the stromal shield, we assessed for the first time the capacity of IL-15 stimulated natural killer (NK) cells to kill PSC and pancreatic cancer cells (PCC). The potency of IL-15 to promote NK cell-mediated killing was evaluated phenotypically and functionally. In addition, NK cell and immune checkpoint ligands on PSC were charted. We demonstrate that IL-15 activated NK cells kill both PCC and PSC lines (range 9-35% and 20-50%, respectively) in a contact-dependent manner and significantly higher as compared to resting NK cells. Improved killing of these pancreatic cell lines is, at least partly, dependent on IL-15 induced upregulation of TIM-3 and NKG2D. Furthermore, we confirm significant killing of primary PSC by IL-15 activated NK cells in an autologous system. Screening for potential targets for immunotherapeutic strategies, we demonstrate surface expression of both inhibitory (PD-L1, PD-L2) and activating (MICA/B, ULBPs and Galectin-9) ligands on primary PSC. These data underscore the therapeutic potential of IL-15 to promote NK cell-mediated cytotoxicity as a treatment of pancreatic cancer and provide promising future targets to tackle remaining PSC.
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http://dx.doi.org/10.18632/oncotarget.18185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5593617PMC
August 2017

Prognostic and predictive aspects of the tumor immune microenvironment and immune checkpoints in malignant pleural mesothelioma.

Oncoimmunology 2017;6(1):e1261241. Epub 2016 Nov 28.

Center for Oncological Research, University of Antwerp, Antwerp, Belgium; Laboratory of Experimental Hematology, Vaccine and Infectious Disease Institute, University of Antwerp, Antwerp, Belgium.

Malignant pleural mesothelioma (MPM) is an aggressive cancer with a poor prognosis and an increasing incidence, for which novel therapeutic strategies are urgently required. Since the immune system has been described to play a presumed role in the protection against MPM, characterization of its tumor immune microenvironment (TME) and immune checkpoints can identify new immunotherapeutic targets and their predictive and/or prognostic value. To characterize the TME and the immune checkpoint expression profile, we performed immunohistochemistry (IHC) on formalin-fixed paraffin embedded (FFPE) tissue sections from 54 MPM patients (40 at time of diagnosis; 14 treated with chemotherapy). We stained for PD-1, PD-L1, TIM-3, LAG-3, CD4, CD8, CD45RO, granzyme B, FoxP3 and CD68. Furthermore, we analyzed the relationship between the immunological parameters and survival, as well as response to chemotherapy. We found that TIM-3, PD-1 and PD-L1 were expressed on both immune and tumor cells. Strikingly, PD-1 and PD-L1 expression on tumor cells was only seen in unpretreated samples. No LAG-3 expression was observed. CD45RO expression in the stroma was an independent negative predictive factor for response on chemotherapy, while CD4 and TIM-3 expression in lymphoid aggregates were independent prognostic factors for better outcome. Our data propose TIM-3 as a promising new target in mesothelioma. Chemotherapy influences the expression of immune checkpoints and therefore further research on the best combination treatment schedule is required.
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http://dx.doi.org/10.1080/2162402X.2016.1261241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5283621PMC
November 2016