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Defining the spatial distribution of extracellular adenosine revealed a myeloid-dependent immunosuppressive microenvironment in pancreatic ductal adenocarcinoma

BACKGROUND: The prognosis for patients with pancreatic ductal adenocarcinoma (PDAC) remains extremely poor. It has been suggested that the adenosine pathway contributes to the ability of PDAC to evade the immune system and hence, its resistance to immuno-oncology therapies (IOT), by generating extra...

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Autores principales: Graziano, Vincenzo, Dannhorn, Andreas, Hulme, Heather, Williamson, Kate, Buckley, Hannah, Karim, Saadia A, Wilson, Matthew, Lee, Sheng Y, Kaistha, Brajesh P, Islam, Sabita, Thaventhiran, James E D, Richards, Frances M, Goodwin, Richard, Brais, Rebecca, Morton, Jennifer P, Dovedi, Simon J, Schuller, Alwin G, Eyles, Jim, Jodrell, Duncan I
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BMJ Publishing Group 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10414095/
https://www.ncbi.nlm.nih.gov/pubmed/37553182
http://dx.doi.org/10.1136/jitc-2022-006457
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author Graziano, Vincenzo
Dannhorn, Andreas
Hulme, Heather
Williamson, Kate
Buckley, Hannah
Karim, Saadia A
Wilson, Matthew
Lee, Sheng Y
Kaistha, Brajesh P
Islam, Sabita
Thaventhiran, James E D
Richards, Frances M
Goodwin, Richard
Brais, Rebecca
Morton, Jennifer P
Dovedi, Simon J
Schuller, Alwin G
Eyles, Jim
Jodrell, Duncan I
author_facet Graziano, Vincenzo
Dannhorn, Andreas
Hulme, Heather
Williamson, Kate
Buckley, Hannah
Karim, Saadia A
Wilson, Matthew
Lee, Sheng Y
Kaistha, Brajesh P
Islam, Sabita
Thaventhiran, James E D
Richards, Frances M
Goodwin, Richard
Brais, Rebecca
Morton, Jennifer P
Dovedi, Simon J
Schuller, Alwin G
Eyles, Jim
Jodrell, Duncan I
author_sort Graziano, Vincenzo
collection PubMed
description BACKGROUND: The prognosis for patients with pancreatic ductal adenocarcinoma (PDAC) remains extremely poor. It has been suggested that the adenosine pathway contributes to the ability of PDAC to evade the immune system and hence, its resistance to immuno-oncology therapies (IOT), by generating extracellular adenosine (eAdo). METHODS: Using genetically engineered allograft models of PDAC in syngeneic mice with defined and different immune infiltration and response to IOT and autochthonous tumors in KPC mice we investigated the impact of the adenosine pathway on the PDAC tumor microenvironment (TME). Flow cytometry and imaging mass cytometry (IMC) were used to characterize the subpopulation frequency and spatial distribution of tumor-infiltrating immune cells. Mass spectrometry imaging (MSI) was used to visualize adenosine compartmentalization in the PDAC tumors. RNA sequencing was used to evaluate the influence of the adenosine pathway on the shaping of the immune milieu and correlate our findings to published data sets in human PDAC. RESULTS: We demonstrated high expression of adenosine pathway components in tumor-infiltrating immune cells (particularly myeloid populations) in the murine models. MSI demonstrated that extracellular adenosine distribution is heterogeneous in tumors, with high concentrations in peri-necrotic, hypoxic regions, associated with rich myeloid infiltration, demonstrated using IMC. Protumorigenic M2 macrophages express high levels of the Adora2a receptor; particularly in the IOT resistant model. Blocking the in vivo formation and function of eAdo (Adoi), using a combination of anti-CD73 antibody and an Adora2a inhibitor slowed tumor growth and reduced metastatic burden. Additionally, blocking the adenosine pathway improved the efficacy of combinations of cytotoxic agents or immunotherapy. Adoi remodeled the TME, by reducing the infiltration of M2 macrophages and regulatory T cells. RNA sequencing analysis showed that genes related to immune modulation, hypoxia and tumor stroma were downregulated following Adoi and a specific adenosine signature derived from this is associated with a poorer prognosis in patients with PDAC. CONCLUSIONS: The formation of eAdo promotes the development of the immunosuppressive TME in PDAC, contributing to its resistance to conventional and novel therapies. Therefore, inhibition of the adenosine pathway may represent a strategy to modulate the PDAC immune milieu and improve therapy response in patients with PDAC.
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spelling pubmed-104140952023-08-11 Defining the spatial distribution of extracellular adenosine revealed a myeloid-dependent immunosuppressive microenvironment in pancreatic ductal adenocarcinoma Graziano, Vincenzo Dannhorn, Andreas Hulme, Heather Williamson, Kate Buckley, Hannah Karim, Saadia A Wilson, Matthew Lee, Sheng Y Kaistha, Brajesh P Islam, Sabita Thaventhiran, James E D Richards, Frances M Goodwin, Richard Brais, Rebecca Morton, Jennifer P Dovedi, Simon J Schuller, Alwin G Eyles, Jim Jodrell, Duncan I J Immunother Cancer Basic Tumor Immunology BACKGROUND: The prognosis for patients with pancreatic ductal adenocarcinoma (PDAC) remains extremely poor. It has been suggested that the adenosine pathway contributes to the ability of PDAC to evade the immune system and hence, its resistance to immuno-oncology therapies (IOT), by generating extracellular adenosine (eAdo). METHODS: Using genetically engineered allograft models of PDAC in syngeneic mice with defined and different immune infiltration and response to IOT and autochthonous tumors in KPC mice we investigated the impact of the adenosine pathway on the PDAC tumor microenvironment (TME). Flow cytometry and imaging mass cytometry (IMC) were used to characterize the subpopulation frequency and spatial distribution of tumor-infiltrating immune cells. Mass spectrometry imaging (MSI) was used to visualize adenosine compartmentalization in the PDAC tumors. RNA sequencing was used to evaluate the influence of the adenosine pathway on the shaping of the immune milieu and correlate our findings to published data sets in human PDAC. RESULTS: We demonstrated high expression of adenosine pathway components in tumor-infiltrating immune cells (particularly myeloid populations) in the murine models. MSI demonstrated that extracellular adenosine distribution is heterogeneous in tumors, with high concentrations in peri-necrotic, hypoxic regions, associated with rich myeloid infiltration, demonstrated using IMC. Protumorigenic M2 macrophages express high levels of the Adora2a receptor; particularly in the IOT resistant model. Blocking the in vivo formation and function of eAdo (Adoi), using a combination of anti-CD73 antibody and an Adora2a inhibitor slowed tumor growth and reduced metastatic burden. Additionally, blocking the adenosine pathway improved the efficacy of combinations of cytotoxic agents or immunotherapy. Adoi remodeled the TME, by reducing the infiltration of M2 macrophages and regulatory T cells. RNA sequencing analysis showed that genes related to immune modulation, hypoxia and tumor stroma were downregulated following Adoi and a specific adenosine signature derived from this is associated with a poorer prognosis in patients with PDAC. CONCLUSIONS: The formation of eAdo promotes the development of the immunosuppressive TME in PDAC, contributing to its resistance to conventional and novel therapies. Therefore, inhibition of the adenosine pathway may represent a strategy to modulate the PDAC immune milieu and improve therapy response in patients with PDAC. BMJ Publishing Group 2023-08-08 /pmc/articles/PMC10414095/ /pubmed/37553182 http://dx.doi.org/10.1136/jitc-2022-006457 Text en © Author(s) (or their employer(s)) 2023. 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 Basic Tumor Immunology
Graziano, Vincenzo
Dannhorn, Andreas
Hulme, Heather
Williamson, Kate
Buckley, Hannah
Karim, Saadia A
Wilson, Matthew
Lee, Sheng Y
Kaistha, Brajesh P
Islam, Sabita
Thaventhiran, James E D
Richards, Frances M
Goodwin, Richard
Brais, Rebecca
Morton, Jennifer P
Dovedi, Simon J
Schuller, Alwin G
Eyles, Jim
Jodrell, Duncan I
Defining the spatial distribution of extracellular adenosine revealed a myeloid-dependent immunosuppressive microenvironment in pancreatic ductal adenocarcinoma
title Defining the spatial distribution of extracellular adenosine revealed a myeloid-dependent immunosuppressive microenvironment in pancreatic ductal adenocarcinoma
title_full Defining the spatial distribution of extracellular adenosine revealed a myeloid-dependent immunosuppressive microenvironment in pancreatic ductal adenocarcinoma
title_fullStr Defining the spatial distribution of extracellular adenosine revealed a myeloid-dependent immunosuppressive microenvironment in pancreatic ductal adenocarcinoma
title_full_unstemmed Defining the spatial distribution of extracellular adenosine revealed a myeloid-dependent immunosuppressive microenvironment in pancreatic ductal adenocarcinoma
title_short Defining the spatial distribution of extracellular adenosine revealed a myeloid-dependent immunosuppressive microenvironment in pancreatic ductal adenocarcinoma
title_sort defining the spatial distribution of extracellular adenosine revealed a myeloid-dependent immunosuppressive microenvironment in pancreatic ductal adenocarcinoma
topic Basic Tumor Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10414095/
https://www.ncbi.nlm.nih.gov/pubmed/37553182
http://dx.doi.org/10.1136/jitc-2022-006457
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