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Anti-CCR4 treatment depletes regulatory T cells and leads to clinical activity in a canine model of advanced prostate cancer

BACKGROUND: Targeting regulatory T cell (Treg) infiltration is an emerging strategy for cancer immunotherapy. However, its efficacy in advanced prostate cancer remains unclear. Here, we showed the therapeutic efficacy of anti-Treg treatment in a canine model of advanced prostate cancer. METHODS: We...

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Autores principales: Maeda, Shingo, Motegi, Tomoki, Iio, Aki, Kaji, Kenjiro, Goto-Koshino, Yuko, Eto, Shotaro, Ikeda, Namiko, Nakagawa, Takayuki, Nishimura, Ryohei, Yonezawa, Tomohiro, Momoi, Yasuyuki
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BMJ Publishing Group 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8804701/
https://www.ncbi.nlm.nih.gov/pubmed/35131860
http://dx.doi.org/10.1136/jitc-2021-003731
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author Maeda, Shingo
Motegi, Tomoki
Iio, Aki
Kaji, Kenjiro
Goto-Koshino, Yuko
Eto, Shotaro
Ikeda, Namiko
Nakagawa, Takayuki
Nishimura, Ryohei
Yonezawa, Tomohiro
Momoi, Yasuyuki
author_facet Maeda, Shingo
Motegi, Tomoki
Iio, Aki
Kaji, Kenjiro
Goto-Koshino, Yuko
Eto, Shotaro
Ikeda, Namiko
Nakagawa, Takayuki
Nishimura, Ryohei
Yonezawa, Tomohiro
Momoi, Yasuyuki
author_sort Maeda, Shingo
collection PubMed
description BACKGROUND: Targeting regulatory T cell (Treg) infiltration is an emerging strategy for cancer immunotherapy. However, its efficacy in advanced prostate cancer remains unclear. Here, we showed the therapeutic efficacy of anti-Treg treatment in a canine model of advanced prostate cancer. METHODS: We used dogs with naturally occurring prostate cancer to study the molecular mechanism underlying Treg infiltration and the effect of anti-Treg treatment. Tumor-infiltrating Tregs was evaluated by immunohistochemistry, and the association with prognosis was examined in dogs with spontaneous prostate cancer. The molecular mechanism of Treg infiltration was explored by RNA sequencing and protein analyses. A non-randomized canine clinical trial was conducted to define the therapeutic potential of anti-Treg treatment for advanced prostate cancer. Human prostate cancer datasets were analyzed to compare gene expression in dogs and humans. RESULTS: Tumor-infiltrating Tregs were associated with poor prognosis in dogs bearing spontaneous prostate cancer. RNA sequencing and protein analyses showed a possible link between the CCL17–CCR4 pathway and the increase of tumor-infiltrating Tregs. Dogs with advanced prostate cancer responded to mogamulizumab, a monoclonal antibody targeting CCR4, with decreased circulating Tregs, improved survival, and low incidence of clinically relevant adverse events. Urinary CCL17 concentration and BRAF(V595E) mutation were independently predictive of the response to mogamulizumab. Analysis of a transcriptomic dataset of human prostate cancer showed that the CCL17–CCR4 axis correlated with Foxp3. In silico survival analyses revealed that high expression of CCL17 was associated with poor prognosis. Immunohistochemistry confirmed that tumor-infiltrating Tregs expressed CCR4 in human patients with prostate cancer. CONCLUSIONS: Anti-Treg treatment, through CCR4 blockade, may be a promising therapeutic approach for advanced prostate cancer in dogs and some population of human patients.
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spelling pubmed-88047012022-02-07 Anti-CCR4 treatment depletes regulatory T cells and leads to clinical activity in a canine model of advanced prostate cancer Maeda, Shingo Motegi, Tomoki Iio, Aki Kaji, Kenjiro Goto-Koshino, Yuko Eto, Shotaro Ikeda, Namiko Nakagawa, Takayuki Nishimura, Ryohei Yonezawa, Tomohiro Momoi, Yasuyuki J Immunother Cancer Clinical/Translational Cancer Immunotherapy BACKGROUND: Targeting regulatory T cell (Treg) infiltration is an emerging strategy for cancer immunotherapy. However, its efficacy in advanced prostate cancer remains unclear. Here, we showed the therapeutic efficacy of anti-Treg treatment in a canine model of advanced prostate cancer. METHODS: We used dogs with naturally occurring prostate cancer to study the molecular mechanism underlying Treg infiltration and the effect of anti-Treg treatment. Tumor-infiltrating Tregs was evaluated by immunohistochemistry, and the association with prognosis was examined in dogs with spontaneous prostate cancer. The molecular mechanism of Treg infiltration was explored by RNA sequencing and protein analyses. A non-randomized canine clinical trial was conducted to define the therapeutic potential of anti-Treg treatment for advanced prostate cancer. Human prostate cancer datasets were analyzed to compare gene expression in dogs and humans. RESULTS: Tumor-infiltrating Tregs were associated with poor prognosis in dogs bearing spontaneous prostate cancer. RNA sequencing and protein analyses showed a possible link between the CCL17–CCR4 pathway and the increase of tumor-infiltrating Tregs. Dogs with advanced prostate cancer responded to mogamulizumab, a monoclonal antibody targeting CCR4, with decreased circulating Tregs, improved survival, and low incidence of clinically relevant adverse events. Urinary CCL17 concentration and BRAF(V595E) mutation were independently predictive of the response to mogamulizumab. Analysis of a transcriptomic dataset of human prostate cancer showed that the CCL17–CCR4 axis correlated with Foxp3. In silico survival analyses revealed that high expression of CCL17 was associated with poor prognosis. Immunohistochemistry confirmed that tumor-infiltrating Tregs expressed CCR4 in human patients with prostate cancer. CONCLUSIONS: Anti-Treg treatment, through CCR4 blockade, may be a promising therapeutic approach for advanced prostate cancer in dogs and some population of human patients. BMJ Publishing Group 2022-01-31 /pmc/articles/PMC8804701/ /pubmed/35131860 http://dx.doi.org/10.1136/jitc-2021-003731 Text en © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ. https://creativecommons.org/licenses/by/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See https://creativecommons.org/licenses/by/4.0/.
spellingShingle Clinical/Translational Cancer Immunotherapy
Maeda, Shingo
Motegi, Tomoki
Iio, Aki
Kaji, Kenjiro
Goto-Koshino, Yuko
Eto, Shotaro
Ikeda, Namiko
Nakagawa, Takayuki
Nishimura, Ryohei
Yonezawa, Tomohiro
Momoi, Yasuyuki
Anti-CCR4 treatment depletes regulatory T cells and leads to clinical activity in a canine model of advanced prostate cancer
title Anti-CCR4 treatment depletes regulatory T cells and leads to clinical activity in a canine model of advanced prostate cancer
title_full Anti-CCR4 treatment depletes regulatory T cells and leads to clinical activity in a canine model of advanced prostate cancer
title_fullStr Anti-CCR4 treatment depletes regulatory T cells and leads to clinical activity in a canine model of advanced prostate cancer
title_full_unstemmed Anti-CCR4 treatment depletes regulatory T cells and leads to clinical activity in a canine model of advanced prostate cancer
title_short Anti-CCR4 treatment depletes regulatory T cells and leads to clinical activity in a canine model of advanced prostate cancer
title_sort anti-ccr4 treatment depletes regulatory t cells and leads to clinical activity in a canine model of advanced prostate cancer
topic Clinical/Translational Cancer Immunotherapy
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8804701/
https://www.ncbi.nlm.nih.gov/pubmed/35131860
http://dx.doi.org/10.1136/jitc-2021-003731
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