Cancer-associated fibroblasts promote pro-tumor functions of neutrophils in pancreatic cancer via IL-8: potential suppression by pirfenidone

Abstract Background The mechanisms by which neutrophils acquire pro-tumor properties remain poorly understood. In pancreatic cancer, cancer-associated fibroblasts (CAFs) may interact with neutrophils, directing them to promote tumor progression. Methods To validate the association between CAFs and n...

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Main Authors: Tomohiko Yagi, Shunsuke Kagawa, Shohei Nogi, Atsuki Taniguchi, Masashi Yoshimoto, Kanto Suemori, Yasuo Nagai, Shuto Fujita, Shinji Kuroda, Satoru Kikuchi, Yoshihiko Kakiuchi, Fuminori Teraishi, Kosei Takagi, Toshiaki Ohara, Hiroshi Tazawa, Toshiyoshi Fujiwara
Format: Article
Language:English
Published: Springer 2025-02-01
Series:Cancer Immunology, Immunotherapy
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Online Access:https://doi.org/10.1007/s00262-025-03946-z
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author Tomohiko Yagi
Shunsuke Kagawa
Shohei Nogi
Atsuki Taniguchi
Masashi Yoshimoto
Kanto Suemori
Yasuo Nagai
Shuto Fujita
Shinji Kuroda
Satoru Kikuchi
Yoshihiko Kakiuchi
Fuminori Teraishi
Kosei Takagi
Toshiaki Ohara
Hiroshi Tazawa
Toshiyoshi Fujiwara
author_facet Tomohiko Yagi
Shunsuke Kagawa
Shohei Nogi
Atsuki Taniguchi
Masashi Yoshimoto
Kanto Suemori
Yasuo Nagai
Shuto Fujita
Shinji Kuroda
Satoru Kikuchi
Yoshihiko Kakiuchi
Fuminori Teraishi
Kosei Takagi
Toshiaki Ohara
Hiroshi Tazawa
Toshiyoshi Fujiwara
author_sort Tomohiko Yagi
collection DOAJ
description Abstract Background The mechanisms by which neutrophils acquire pro-tumor properties remain poorly understood. In pancreatic cancer, cancer-associated fibroblasts (CAFs) may interact with neutrophils, directing them to promote tumor progression. Methods To validate the association between CAFs and neutrophils, the localization of neutrophils was examined in clinically resected pancreatic cancer specimens. CAFs were produced by culturing in cancer-conditioned media, and the effects of these CAFs on neutrophils were examined. In vitro migration and invasion assays assess the effect of CAF-activated neutrophils on cancer cells. The factors secreted by the activated neutrophils were also explored. Finally, pirfenidone (PFD) was tested to determine whether it could suppress the pro-tumor functions of activated neutrophils. Results In pancreatic cancer specimens, neutrophils tended to co-localize with IL-6-positive CAFs. Neutrophils co-cultured with CAFs increased migratory capacity and prolonged life span. CAF-affected neutrophils enhance the migratory and invasive activities of pancreatic cancer cells. IL-8 is the most upregulated cytokine secreted by the neutrophils. PFD suppresses IL-8 secretion from CAF-stimulated neutrophils and mitigates the malignant traits of pancreatic cancer cells. Conclusion CAFs activate neutrophils and enhance the malignant phenotype of pancreatic cancer. The interactions between cancer cells, CAFs, and neutrophils can be disrupted by PFD, highlighting a potential therapeutic approach.
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spelling doaj-art-09406a143fe443739c939588b8bfc7972025-02-09T12:39:14ZengSpringerCancer Immunology, Immunotherapy1432-08512025-02-0174311110.1007/s00262-025-03946-zCancer-associated fibroblasts promote pro-tumor functions of neutrophils in pancreatic cancer via IL-8: potential suppression by pirfenidoneTomohiko Yagi0Shunsuke Kagawa1Shohei Nogi2Atsuki Taniguchi3Masashi Yoshimoto4Kanto Suemori5Yasuo Nagai6Shuto Fujita7Shinji Kuroda8Satoru Kikuchi9Yoshihiko Kakiuchi10Fuminori Teraishi11Kosei Takagi12Toshiaki Ohara13Hiroshi Tazawa14Toshiyoshi Fujiwara15Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesDepartments of Pathology and Experimental Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesDepartment of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesAbstract Background The mechanisms by which neutrophils acquire pro-tumor properties remain poorly understood. In pancreatic cancer, cancer-associated fibroblasts (CAFs) may interact with neutrophils, directing them to promote tumor progression. Methods To validate the association between CAFs and neutrophils, the localization of neutrophils was examined in clinically resected pancreatic cancer specimens. CAFs were produced by culturing in cancer-conditioned media, and the effects of these CAFs on neutrophils were examined. In vitro migration and invasion assays assess the effect of CAF-activated neutrophils on cancer cells. The factors secreted by the activated neutrophils were also explored. Finally, pirfenidone (PFD) was tested to determine whether it could suppress the pro-tumor functions of activated neutrophils. Results In pancreatic cancer specimens, neutrophils tended to co-localize with IL-6-positive CAFs. Neutrophils co-cultured with CAFs increased migratory capacity and prolonged life span. CAF-affected neutrophils enhance the migratory and invasive activities of pancreatic cancer cells. IL-8 is the most upregulated cytokine secreted by the neutrophils. PFD suppresses IL-8 secretion from CAF-stimulated neutrophils and mitigates the malignant traits of pancreatic cancer cells. Conclusion CAFs activate neutrophils and enhance the malignant phenotype of pancreatic cancer. The interactions between cancer cells, CAFs, and neutrophils can be disrupted by PFD, highlighting a potential therapeutic approach.https://doi.org/10.1007/s00262-025-03946-zCancer-associated fibroblastsNeutrophilAnti-fibrotic agentPirfenidone
spellingShingle Tomohiko Yagi
Shunsuke Kagawa
Shohei Nogi
Atsuki Taniguchi
Masashi Yoshimoto
Kanto Suemori
Yasuo Nagai
Shuto Fujita
Shinji Kuroda
Satoru Kikuchi
Yoshihiko Kakiuchi
Fuminori Teraishi
Kosei Takagi
Toshiaki Ohara
Hiroshi Tazawa
Toshiyoshi Fujiwara
Cancer-associated fibroblasts promote pro-tumor functions of neutrophils in pancreatic cancer via IL-8: potential suppression by pirfenidone
Cancer Immunology, Immunotherapy
Cancer-associated fibroblasts
Neutrophil
Anti-fibrotic agent
Pirfenidone
title Cancer-associated fibroblasts promote pro-tumor functions of neutrophils in pancreatic cancer via IL-8: potential suppression by pirfenidone
title_full Cancer-associated fibroblasts promote pro-tumor functions of neutrophils in pancreatic cancer via IL-8: potential suppression by pirfenidone
title_fullStr Cancer-associated fibroblasts promote pro-tumor functions of neutrophils in pancreatic cancer via IL-8: potential suppression by pirfenidone
title_full_unstemmed Cancer-associated fibroblasts promote pro-tumor functions of neutrophils in pancreatic cancer via IL-8: potential suppression by pirfenidone
title_short Cancer-associated fibroblasts promote pro-tumor functions of neutrophils in pancreatic cancer via IL-8: potential suppression by pirfenidone
title_sort cancer associated fibroblasts promote pro tumor functions of neutrophils in pancreatic cancer via il 8 potential suppression by pirfenidone
topic Cancer-associated fibroblasts
Neutrophil
Anti-fibrotic agent
Pirfenidone
url https://doi.org/10.1007/s00262-025-03946-z
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