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CANCER-ASSOCIATED FIBROBLASTS REGULATE THE FORMATION OF MACROPHAGE EXTRACELLULAR TRAPS VIA CCL11/CCR5 AXIS TO RESIST IMMUNOTHERAPY IN PANCREATIC DUCTAL ADENOCARCINOMA

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CANCER-ASSOCIATED FIBROBLASTS REGULATE THE FORMATION OF MACROPHAGE EXTRACELLULAR TRAPS VIA CCL11/CCR5 AXIS TO RESIST IMMUNOTHERAPY IN PANCREATIC DUCTAL ADENOCARCINOMA

Zhao Shi 1, Quan Zhou 2, Kun Liu 2, Yihang Jiang 2, Shuang Nie 2, Yuanyuan Yu 2, Lei Wang 2, Xiaoping Zou 2, Shanshan Shen 2, Hongzhen Li 2

Affiliations

1 Clinical College of Nanjing Medical University, Nanjing, China

2 The Affiliated Hospital of Nanjing University Medical School, Nanjing, China

Summary

AI Generated

Cancer-associated fibroblasts promote macrophage extracellular trap formation via CCL11/CCR5 signaling in pancreatic cancer, and the CCR5 inhibitor maraviroc suppresses METs formation and enhances immunotherapy efficacy in preclinical models.

High levels of macrophage extracellular traps (METs) in pancreatic ductal adenocarcinoma tissue were significantly associated with poor patient survival, advanced tumor grade and stage, fewer infiltrating CD8+ T-cells, increased CD86+ macrophages, and increased α-SMA+ cancer-associated fibroblasts in 46 surgical samples.
CCL11 secreted by cancer-associated fibroblasts bound to CCR5 on macrophages and promoted PAD2 expression, facilitating METs formation.
Maraviroc, a CCR5 inhibitor, effectively suppressed METs formation and increased PD-L1 expression and CD8+ T cell infiltration in pancreatic cancer tissue.
In mouse orthotopic transplantation models using KPC-derived organoids, maraviroc effectively enhanced the anti-tumor effects of immunotherapy.
The findings suggest that antagonizing CCR5 to inhibit METs formation reshaped the immunosuppressive microenvironment of pancreatic cancer and enhanced sensitivity to immunotherapy.

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Abstract

Introduction

Pancreatic ductal adenocarcinoma (PDAC) is the most lethal malignancy with limited effective treatments options. PDAC remains resistant to immunotherapy due to its immunosuppressive tumor microenvironment and dense desmoplastic stroma，which are attributed to an abundance of cancer associated fibroblasts (CAFs) and infiltrating immunocytes. Macrophages release extracellular traps which are composed of a backbone of extracellular DNA fibers containing histones and cytotoxic proteases such as myeloperoxidase, elastase, and matrix metalloproteinase in order to exert local immunoregulation. However, the role of macrophages extracellular traps (METs) in PDAC is at present unclear.

Aims & Methods

METs expression was evaluated in human PDAC tissues using Immunofluorescence co-localization of citrullinated histone H3 (H3cit) and CD68. Patients cohorts were classified into METs-High and METs-Low groups based on their numbers of postive cells. The collagen deposition and infiltrating immune cell populations were detected by Immunohistochemistry in both human and mice PDAC tissues. Cytokine production in human serum was assayed using the Olink proteomic platform. The level of C-C motif chemokine ligand 11 (CCL11) and double-stranded DNA (dsDNA) in serum and conditioned medium were determined by ELISA. Pancreatic orthotopic transplantation tumors were constructed using panc02 cell line and organoids derived from KrasG12D/+; Trp53R172H/+; Pdx1Cre (KPC) mouse PDAC tissue. Western blot and q-PCR were utilized to validate the expression levels of CAFs and METs markers across different groups. T cell activation, macrophage phenotype and programmed death-ligand 1 (PD-L1) level in mouse pancreatic tumors were evaluated by flow cytometry.

Results

The METs level was elevated in PDAC compared to paracancerous tissues and it was significantly linked to poor patient survival, advanced tumor grade and stage, fewer infiltrating CD8+ T-cells, increased CD86+ macrophages, and increased α-SMA+ CAFs. CCL11, secreted by CAFs, was a key upstream signaling molecule for METs formation. Mechanistically, CCL11 binded to chemokine receptor 5 (CCR5) on the surface of macrophages and promoted PAD2 expression, facilitating MET formation. Maraviroc, a CCR5 inhibitor, effectively suppressed this process and increased the expression of PD-L1 and the infiltration of CD8+ T cells in PDAC tissue. In vivo, maraviroc effectively enhanced the anti-tumor effects of immunotherapy.

Conclusion

CAFs promoted the formation of METs via CCL11/CCR5 axis and further contributed to the formation of an immunosuppressive microenvironment in PDAC. Through the inhibition of METs formation by antagonizing CCR5 reshaped the immune microenvironment of PDAC and enhanced the sensitivity of immunotherapy.

Event

UEG Week Vienna 2024

Topics

Digestive Oncology Endoscopy Immunology Mechanisms & Personalised Medicine Pancreas Radiology & Imaging

Submission format

Abstract

Session

Pancreatic diseases: From models to precision medicine

Citation

United European Gastroenterology Journal 2024; 12 (Supplement 8)

Published

2024

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Does autoimmune pancreatitis type III exist?

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Alexander Kleger 1

Affiliations

1 Institute of Molecular Oncology and Stem Cell Biology, Ulm University Hospital, Ulm, Germany

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Abstract

Event

UEG Week Berlin 2025

Topics

Hepatobiliary Immunology Pancreas

Session

Developments in autoimmune HPB disease

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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Pancreas necrosis: What to do after initial drainage

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Pancreas necrosis: What to do after initial drainage

Robert C. Verdonk 1

Affiliations

1 St. Antonius Ziekenhuis, Nieuwegein, Netherlands

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Abstract

Event

UEG Week Berlin 2025

Topics

Nurses Pancreas Radiology & Imaging

Session

Hot topics in European gastroenterology

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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Share via Email Share on Facebook Share on X Share on LinkedIn Share on Bluesky

Persistent lipase and localised damage: Cause or consequence?

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Persistent lipase and localised damage: Cause or consequence?

Peter Hegyi 1

Affiliations

1 University of Pecs, Pecs, Hungary

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Abstract

Event

UEG Week Berlin 2025

Topics

Endoscopy Pancreas

Session

Therapy update: Acute severe pancreatitis – It's all about timing!

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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Endoscopic ultrasound in BD-IPMN: Cytology, histology, endo-microscopy or molecular biology?

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Endoscopic ultrasound in BD-IPMN: Cytology, histology, endo-microscopy or molecular biology?

Kasper Overbeek 1

Affiliations

1 Erasmus MC Cancer Institute, University Medical Center, Rotterdam, Netherlands

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Abstract

Event

UEG Postgraduate Teaching Programme Berlin 2025

Topics

Endoscopy Histopathology Pancreas

Session

Cystic pancreatic lesions

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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Panel discussion: Acute severe pancreatitis

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Panel discussion: Acute severe pancreatitis

Marco J. Bruno 1, Jacob Hamm 2, Peter Hegyi 3, Jayanta Samanta 4

Affiliations

1 Eramus University Medical Centre, Rotterdam, Netherlands

2 University Medical Center Goettingen, Goettingen, Germany

3 University of Pecs, Pecs, Hungary

4 Post Graduate Institute of Medical Education and Research, Chandigarh, Kolkata, India

Summary

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Abstract

Event

UEG Week Berlin 2025

Topics

Endoscopy Pancreas

Session

Therapy update: Acute severe pancreatitis – It's all about timing!

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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UEG Poster

Standard Poster

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MICROBIOTA IN PATIENTS WITH CELIAC DISEASE: FROM DIAGNOSIS TO FOLLOW-UP

Michela Palo 1, Elena Agostini 1, Anna Pretto 2, Cristina Caranfil 2, Sonia Facchin 2, Edoardo Vincenzo Savarino 3, Fabiana Zingone 2

Affiliations

1 University Of Padua, Padua, Italy

2 University of Padua, Padua, Italy

3 University of Padua, Division of Gastroenterology, Padua, Italy

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Abstract

Introduction

The intestinal microbiota is defined as the community of microorganisms inhabiting the gastrointestinal tract, which confer benefits to the organism and play a role in immune system regulation. It has been suggested that the microbiota may play a role in the pathogenesis of gut diseases, including Celiac Disease (CeD), and the response to a gluten free diet (GFD). (1) Intestinal dysbiosis may be a contributing factor to the inflammatory state, thereby hindering resolution of symptoms and complete mucosal healing, particularly in patients who show a lack of clinical and histological improvement despite following a GFD. (2,3).

Aims & Methods

We aimed to provide a preliminary evaluation of the gut microbiota profile from diagnosis to follow-up, classifying patients who respond and do not respond to diet in order to establish a first baseline of the microbial composition and its relationship to the dietary response.
We collected fecal samples from patients enrolled at the Gastroenterology Unit of Azienda Ospedale- Università of Padova, from March to November 2024. All patients needed to be off antibiotics, probiotics and proton-pump inhibitors for at least one month before enrolment. Stool samples were collected and transferred in a buffer solution, and stored at -20°C.
Fecal samples were analyzed by BMR Genomic s.r.l. (Padua, Italy) that sequenced the V3-V4 hypervariable 16S ribosomal RNA region using the Illumina MiSeq. The results were compared to an internal population of healthy subjects (provided by BMR genomics) using Qiime2 tools. Statistical analysis was conducted using STATA 18 software. Categorical variables were compared using the Chi-square test, while non-parametric continuous variables were analysed using the Mann-Whitney test.

Results

We enrolled 71 CeD patients with mean age at diagnosis of 35.76 ± 16.29 years old (50 out of 71 were female). Of the 71 patients, 9 were newly diagnosed with CeD, while 62 were in follow-up. Among follow-up groups, 44 of 62 patients (71%) were classified as responders to diet and 18 (29%) were classified as non- responders, exhibiting classical symptoms, positive serology and histology. We compared the relative abundance of the main bacterial phyla in each sample: a significant decrease in beneficial phyla such as Actinobacteria (p = 0.04) and a decrease close to the significant threshold in Firmicutes (p = 0.06) was observed after the follow-up. This factor could be ascribed to a long-term dietary regime rather than to the disease itself. (4) Proteobacteria were more abundant in follow-up, especially in non-responders. This phylum includes many potentially pathogenic microorganisms belonging to Escherichia, Klebsiella and Shigella genera. Comparing diagnosis and follow-up patients, Clostridium perfringens was significantly more present in patients during follow-up (p=0.02), while Escherichia coli showed greater presence in patients at diagnosis (p=0.035) and in non-responders, consistently with his role in the inflammatory phase of the disease. (5)

Conclusion

Our preliminary data suggest that a long-term GFD does not always restore completely the intestinal dysbiosis present at the diagnosis and could be associated with specific alterations in beneficial bacteria. The presence of abundant Proteobacteria at diagnosis and in non-responder patients may be considered as biomarkers of active state of CeD. Future studies on various biological samples, as well as a more extensive investigation into the impact of long-term GFD, are required to highlight microbiota-immunity relationships involved in development of CeD.

References

Zafeiropoulou K, Nichols B, Mackinder M, et al. Alterations in intestinal microbiota of children with celiac disease at the time of diagnosis and on a gluten-free diet. Gastroenterology. 2020;159(6):2039–2051.e20.
Freire R, Ferreira R, Almeida LM, et al. Human gut-derived organoids provide model to study gluten response and effects of microbiota-derived molecules in celiac disease. Sci Rep. 2019;9(1):1–12
Schiepatti A, Montagnani M, D'Argenio V, et al. Relationship between duodenal microbiota composition, clinical features at diagnosis, and persistent symptoms in adult celiac disease. Front Microbiol. 2021;12:1–12
Wacklin P, Nikkilä J, Tuovinen E, et al. Altered duodenal microbiota composition in celiac disease patients suffering from persistent symptoms on a long-term gluten-free diet. Am J Gastroenterol. 2014;109(10):1587–1594
Olshan KL, Leonard MM, Serena G, Zomorrodi AR, Fasano A. Gut microbiota in celiac disease: microbes, metabolites, pathways and therapeutics. Expert Rev Clin Immunol. 2020 Nov;16(11):1075-1092.

Conference

UEG Week Berlin 2025

Topics

Small Intestine & Nutrition

Submission format

Abstract

Session

SMALL INTESTINAL (Posters)

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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UEG's educational platform for gastroenterology education bringing recordings, courses, guidelines, and more together in one place.

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