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CCR2/CCR5 inhibitor permits the radiation-induced effector T cell infiltration in pancreatic adenocarcinoma

The resistance of pancreatic ductal adenocarcinoma (PDAC) to immune checkpoint inhibitors (ICIs) is attributed to the immune-quiescent and -suppressive tumor microenvironment (TME). We recently found that CCR2 and CCR5 were induced in PDAC following treatment with anti–PD-1 antibody (αPD-1); thus, w...

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Autores principales: Wang, Jianxin, Saung, May Tun, Li, Keyu, Fu, Juan, Fujiwara, Kenji, Niu, Nan, Muth, Stephen, Wang, Junke, Xu, Yao, Rozich, Noah, Zlomke, Haley, Chen, Sophia, Espinoza, Birginia, Henderson, MacKenzie, Funes, Vanessa, Herbst, Brian, Ding, Ding, Twyman-Saint Victor, Christina, Zhao, Qihong, Narang, Amol, He, Jin, Zheng, Lei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Rockefeller University Press 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9006312/
https://www.ncbi.nlm.nih.gov/pubmed/35404390
http://dx.doi.org/10.1084/jem.20211631
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author Wang, Jianxin
Saung, May Tun
Li, Keyu
Fu, Juan
Fujiwara, Kenji
Niu, Nan
Muth, Stephen
Wang, Junke
Xu, Yao
Rozich, Noah
Zlomke, Haley
Chen, Sophia
Espinoza, Birginia
Henderson, MacKenzie
Funes, Vanessa
Herbst, Brian
Ding, Ding
Twyman-Saint Victor, Christina
Zhao, Qihong
Narang, Amol
He, Jin
Zheng, Lei
author_facet Wang, Jianxin
Saung, May Tun
Li, Keyu
Fu, Juan
Fujiwara, Kenji
Niu, Nan
Muth, Stephen
Wang, Junke
Xu, Yao
Rozich, Noah
Zlomke, Haley
Chen, Sophia
Espinoza, Birginia
Henderson, MacKenzie
Funes, Vanessa
Herbst, Brian
Ding, Ding
Twyman-Saint Victor, Christina
Zhao, Qihong
Narang, Amol
He, Jin
Zheng, Lei
author_sort Wang, Jianxin
collection PubMed
description The resistance of pancreatic ductal adenocarcinoma (PDAC) to immune checkpoint inhibitors (ICIs) is attributed to the immune-quiescent and -suppressive tumor microenvironment (TME). We recently found that CCR2 and CCR5 were induced in PDAC following treatment with anti–PD-1 antibody (αPD-1); thus, we examined PDAC vaccine or radiation therapy (RT) as T cell priming mechanisms together with BMS-687681, a dual antagonist of CCR2 and CCR5 (CCR2/5i), in combination with αPD-1 as new treatment strategies. Using PDAC mouse models, we demonstrated that RT followed by αPD-1 and prolonged treatment with CCR2/5i conferred better antitumor efficacy than other combination treatments tested. The combination of RT + αPD-1 + CCR2/5i enhanced intratumoral effector and memory T cell infiltration but suppressed regulatory T cell, M2-like tumor–associated macrophage, and myeloid-derived suppressive cell infiltration. RNA sequencing showed that CCR2/5i partially inhibited RT-induced TLR2/4 and RAGE signaling, leading to decreased expression of immunosuppressive cytokines including CCL2/CCL5, but increased expression of effector T cell chemokines such as CCL17/CCL22. This study thus supports the clinical development of CCR2/5i in combination with RT and ICIs for PDAC treatment.
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spelling pubmed-90063122022-04-27 CCR2/CCR5 inhibitor permits the radiation-induced effector T cell infiltration in pancreatic adenocarcinoma Wang, Jianxin Saung, May Tun Li, Keyu Fu, Juan Fujiwara, Kenji Niu, Nan Muth, Stephen Wang, Junke Xu, Yao Rozich, Noah Zlomke, Haley Chen, Sophia Espinoza, Birginia Henderson, MacKenzie Funes, Vanessa Herbst, Brian Ding, Ding Twyman-Saint Victor, Christina Zhao, Qihong Narang, Amol He, Jin Zheng, Lei J Exp Med Article The resistance of pancreatic ductal adenocarcinoma (PDAC) to immune checkpoint inhibitors (ICIs) is attributed to the immune-quiescent and -suppressive tumor microenvironment (TME). We recently found that CCR2 and CCR5 were induced in PDAC following treatment with anti–PD-1 antibody (αPD-1); thus, we examined PDAC vaccine or radiation therapy (RT) as T cell priming mechanisms together with BMS-687681, a dual antagonist of CCR2 and CCR5 (CCR2/5i), in combination with αPD-1 as new treatment strategies. Using PDAC mouse models, we demonstrated that RT followed by αPD-1 and prolonged treatment with CCR2/5i conferred better antitumor efficacy than other combination treatments tested. The combination of RT + αPD-1 + CCR2/5i enhanced intratumoral effector and memory T cell infiltration but suppressed regulatory T cell, M2-like tumor–associated macrophage, and myeloid-derived suppressive cell infiltration. RNA sequencing showed that CCR2/5i partially inhibited RT-induced TLR2/4 and RAGE signaling, leading to decreased expression of immunosuppressive cytokines including CCL2/CCL5, but increased expression of effector T cell chemokines such as CCL17/CCL22. This study thus supports the clinical development of CCR2/5i in combination with RT and ICIs for PDAC treatment. Rockefeller University Press 2022-04-11 /pmc/articles/PMC9006312/ /pubmed/35404390 http://dx.doi.org/10.1084/jem.20211631 Text en © 2022 Wang et al. https://creativecommons.org/licenses/by/4.0/This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Wang, Jianxin
Saung, May Tun
Li, Keyu
Fu, Juan
Fujiwara, Kenji
Niu, Nan
Muth, Stephen
Wang, Junke
Xu, Yao
Rozich, Noah
Zlomke, Haley
Chen, Sophia
Espinoza, Birginia
Henderson, MacKenzie
Funes, Vanessa
Herbst, Brian
Ding, Ding
Twyman-Saint Victor, Christina
Zhao, Qihong
Narang, Amol
He, Jin
Zheng, Lei
CCR2/CCR5 inhibitor permits the radiation-induced effector T cell infiltration in pancreatic adenocarcinoma
title CCR2/CCR5 inhibitor permits the radiation-induced effector T cell infiltration in pancreatic adenocarcinoma
title_full CCR2/CCR5 inhibitor permits the radiation-induced effector T cell infiltration in pancreatic adenocarcinoma
title_fullStr CCR2/CCR5 inhibitor permits the radiation-induced effector T cell infiltration in pancreatic adenocarcinoma
title_full_unstemmed CCR2/CCR5 inhibitor permits the radiation-induced effector T cell infiltration in pancreatic adenocarcinoma
title_short CCR2/CCR5 inhibitor permits the radiation-induced effector T cell infiltration in pancreatic adenocarcinoma
title_sort ccr2/ccr5 inhibitor permits the radiation-induced effector t cell infiltration in pancreatic adenocarcinoma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9006312/
https://www.ncbi.nlm.nih.gov/pubmed/35404390
http://dx.doi.org/10.1084/jem.20211631
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