Fibroblast activation protein targeted near infrared photoimmunotherapy (NIR PIT) overcomes therapeutic resistance in human esophageal cancer

Abstract Cancer-associated fibroblasts (CAFs) have an important role in the tumor microenvironment. CAFs have the multifunctionality which strongly support cancer progression and the acquisition of therapeutic resistance by cancer cells. Near-infrared photoimmunotherapy (NIR-PIT) is a novel cancer t...

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Autores principales:	Ryoichi Katsube, Kazuhiro Noma, Toshiaki Ohara, Noriyuki Nishiwaki, Teruki Kobayashi, Satoshi Komoto, Hiroaki Sato, Hajime Kashima, Takuya Kato, Satoru Kikuchi, Hiroshi Tazawa, Shunsuke Kagawa, Yasuhiro Shirakawa, Hisataka Kobayashi, Toshiyoshi Fujiwara
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/edf5fed397e64f0e8fa9e8ebc6976513
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spelling	oai:doaj.org-article:edf5fed397e64f0e8fa9e8ebc69765132021-12-02T11:50:40ZFibroblast activation protein targeted near infrared photoimmunotherapy (NIR PIT) overcomes therapeutic resistance in human esophageal cancer10.1038/s41598-021-81465-42045-2322https://doaj.org/article/edf5fed397e64f0e8fa9e8ebc69765132021-01-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-81465-4https://doaj.org/toc/2045-2322Abstract Cancer-associated fibroblasts (CAFs) have an important role in the tumor microenvironment. CAFs have the multifunctionality which strongly support cancer progression and the acquisition of therapeutic resistance by cancer cells. Near-infrared photoimmunotherapy (NIR-PIT) is a novel cancer treatment that uses a highly selective monoclonal antibody (mAb)-photosensitizer conjugate. We developed fibroblast activation protein (FAP)-targeted NIR-PIT, in which IR700 was conjugated to a FAP-specific antibody to target CAFs (CAFs-targeted NIR-PIT: CAFs-PIT). Thus, we hypothesized that the control of CAFs could overcome the resistance to conventional chemotherapy in esophageal cancer (EC). In this study, we evaluated whether EC cell acquisition of stronger malignant characteristics and refractoriness to chemoradiotherapy are mediated by CAFs. Next, we assessed whether the resistance could be rescued by eliminating CAF stimulation by CAFs-PIT in vitro and in vivo. Cancer cells acquired chemoradiotherapy resistance via CAF stimulation in vitro and 5-fluorouracil (FU) resistance in CAF-coinoculated tumor models in vivo. CAF stimulation promoted the migration/invasion of cancer cells and a stem-like phenotype in vitro, which were rescued by elimination of CAF stimulation. CAFs-PIT had a highly selective effect on CAFs in vitro. Finally, CAF elimination by CAFs-PIT in vivo demonstrated that the combination of 5-FU and NIR-PIT succeeded in producing 70.9% tumor reduction, while 5-FU alone achieved only 13.3% reduction, suggesting the recovery of 5-FU sensitivity in CAF-rich tumors. In conclusion, CAFs-PIT could overcome therapeutic resistance via CAF elimination. The combined use of novel targeted CAFs-PIT with conventional anticancer treatments can be expected to provide a more effective and sensible treatment strategy.Ryoichi KatsubeKazuhiro NomaToshiaki OharaNoriyuki NishiwakiTeruki KobayashiSatoshi KomotoHiroaki SatoHajime KashimaTakuya KatoSatoru KikuchiHiroshi TazawaShunsuke KagawaYasuhiro ShirakawaHisataka KobayashiToshiyoshi FujiwaraNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-16 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Ryoichi Katsube Kazuhiro Noma Toshiaki Ohara Noriyuki Nishiwaki Teruki Kobayashi Satoshi Komoto Hiroaki Sato Hajime Kashima Takuya Kato Satoru Kikuchi Hiroshi Tazawa Shunsuke Kagawa Yasuhiro Shirakawa Hisataka Kobayashi Toshiyoshi Fujiwara Fibroblast activation protein targeted near infrared photoimmunotherapy (NIR PIT) overcomes therapeutic resistance in human esophageal cancer
description	Abstract Cancer-associated fibroblasts (CAFs) have an important role in the tumor microenvironment. CAFs have the multifunctionality which strongly support cancer progression and the acquisition of therapeutic resistance by cancer cells. Near-infrared photoimmunotherapy (NIR-PIT) is a novel cancer treatment that uses a highly selective monoclonal antibody (mAb)-photosensitizer conjugate. We developed fibroblast activation protein (FAP)-targeted NIR-PIT, in which IR700 was conjugated to a FAP-specific antibody to target CAFs (CAFs-targeted NIR-PIT: CAFs-PIT). Thus, we hypothesized that the control of CAFs could overcome the resistance to conventional chemotherapy in esophageal cancer (EC). In this study, we evaluated whether EC cell acquisition of stronger malignant characteristics and refractoriness to chemoradiotherapy are mediated by CAFs. Next, we assessed whether the resistance could be rescued by eliminating CAF stimulation by CAFs-PIT in vitro and in vivo. Cancer cells acquired chemoradiotherapy resistance via CAF stimulation in vitro and 5-fluorouracil (FU) resistance in CAF-coinoculated tumor models in vivo. CAF stimulation promoted the migration/invasion of cancer cells and a stem-like phenotype in vitro, which were rescued by elimination of CAF stimulation. CAFs-PIT had a highly selective effect on CAFs in vitro. Finally, CAF elimination by CAFs-PIT in vivo demonstrated that the combination of 5-FU and NIR-PIT succeeded in producing 70.9% tumor reduction, while 5-FU alone achieved only 13.3% reduction, suggesting the recovery of 5-FU sensitivity in CAF-rich tumors. In conclusion, CAFs-PIT could overcome therapeutic resistance via CAF elimination. The combined use of novel targeted CAFs-PIT with conventional anticancer treatments can be expected to provide a more effective and sensible treatment strategy.
format	article
author	Ryoichi Katsube Kazuhiro Noma Toshiaki Ohara Noriyuki Nishiwaki Teruki Kobayashi Satoshi Komoto Hiroaki Sato Hajime Kashima Takuya Kato Satoru Kikuchi Hiroshi Tazawa Shunsuke Kagawa Yasuhiro Shirakawa Hisataka Kobayashi Toshiyoshi Fujiwara
author_facet	Ryoichi Katsube Kazuhiro Noma Toshiaki Ohara Noriyuki Nishiwaki Teruki Kobayashi Satoshi Komoto Hiroaki Sato Hajime Kashima Takuya Kato Satoru Kikuchi Hiroshi Tazawa Shunsuke Kagawa Yasuhiro Shirakawa Hisataka Kobayashi Toshiyoshi Fujiwara
author_sort	Ryoichi Katsube
title	Fibroblast activation protein targeted near infrared photoimmunotherapy (NIR PIT) overcomes therapeutic resistance in human esophageal cancer
title_short	Fibroblast activation protein targeted near infrared photoimmunotherapy (NIR PIT) overcomes therapeutic resistance in human esophageal cancer
title_full	Fibroblast activation protein targeted near infrared photoimmunotherapy (NIR PIT) overcomes therapeutic resistance in human esophageal cancer
title_fullStr	Fibroblast activation protein targeted near infrared photoimmunotherapy (NIR PIT) overcomes therapeutic resistance in human esophageal cancer
title_full_unstemmed	Fibroblast activation protein targeted near infrared photoimmunotherapy (NIR PIT) overcomes therapeutic resistance in human esophageal cancer
title_sort	fibroblast activation protein targeted near infrared photoimmunotherapy (nir pit) overcomes therapeutic resistance in human esophageal cancer
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/edf5fed397e64f0e8fa9e8ebc6976513
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Fibroblast activation protein targeted near infrared photoimmunotherapy (NIR PIT) overcomes therapeutic resistance in human esophageal cancer

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