TY - JOUR
T1 - The resurgence of the Adora2b receptor as an immunotherapeutic target in pancreatic cancer
AU - Strickland, Lincoln N.
AU - Faraoni, Erika Y.
AU - Ruan, Wei
AU - Yuan, Xiaoyi
AU - Eltzschig, Holger K.
AU - Bailey-Lundberg, Jennifer M.
N1 - Funding Information:
Natural Science Foundation of Hunan Province Grant 2018JJ3736, Young Talent Foundation of Hunan Province Grant 2021RC3034, and 2022 International Anesthesia Research Society Mentored Research Award to WR. National Institute of Health Grants R01HL155950, and Parker B. Francis Fellowship to XY. National Institute of Health Grants R01HL154720, R01DK122796, R01HL133900, T32GM135118 and Department of Defense Grant W81XWH2110032 to HE; sponsored contract through Akebia Therapeutics, Inc. to HE. JB-L is funded by NIH grants Texas Medical Center Digestive Disease Center Pilot Award 2P30DK056338-16 and 1R21CA249924-01. The funder, Akebia Therapeutics Inc., was not involved in the study design, collection, analysis, interpretation of data, the writing of this article, or the decision to submit it for publication.
Funding Information:
Natural Science Foundation of Hunan Province Grant 2018JJ3736, Young Talent Foundation of Hunan Province Grant 2021RC3034, and 2022 International Anesthesia Research Society Mentored Research Award to WR. National Institute of Health Grants R01HL155950, and Parker B. Francis Fellowship to XY. National Institute of Health Grants R01HL154720, R01DK122796, R01HL133900, T32GM135118 and Department of Defense Grant W81XWH2110032 to HE; sponsored contract through Akebia Therapeutics, Inc. to HE. JB-L is funded by NIH grants Texas Medical Center Digestive Disease Center Pilot Award 2P30DK056338-16 and 1R21CA249924-01. The funder, Akebia Therapeutics Inc., was not involved in the study design, collection, analysis, interpretation of data, the writing of this article, or the decision to submit it for publication. Acknowledgments
Publisher Copyright:
Copyright © 2023 Strickland, Faraoni, Ruan, Yuan, Eltzschig and Bailey-Lundberg.
PY - 2023
Y1 - 2023
N2 - Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense desmoplastic stroma that impedes drug delivery, reduces parenchymal blood flow, and suppresses the anti-tumor immune response. The extracellular matrix and abundance of stromal cells result in severe hypoxia within the tumor microenvironment (TME), and emerging publications evaluating PDAC tumorigenesis have shown the adenosine signaling pathway promotes an immunosuppressive TME and contributes to the overall low survival rate. Hypoxia increases many elements of the adenosine signaling pathway, resulting in higher adenosine levels in the TME, further contributing to immune suppression. Extracellular adenosine signals through 4 adenosine receptors (Adora1, Adora2a, Adora2b, Adora3). Of the 4 receptors, Adora2b has the lowest affinity for adenosine and thus, has important consequences when stimulated by adenosine binding in the hypoxic TME. We and others have shown that Adora2b is present in normal pancreas tissue, and in injured or diseased pancreatic tissue, Adora2b levels are significantly elevated. The Adora2b receptor is present on many immune cells, including macrophages, dendritic cells, natural killer cells, natural killer T cells, γδ T cells, B cells, T cells, CD4+ T cells, and CD8+ T cells. In these immune cell types, adenosine signaling through Adora2b can reduce the adaptive anti-tumor response, augmenting immune suppression, or may contribute to transformation and changes in fibrosis, perineural invasion, or the vasculature by binding the Adora2b receptor on neoplastic epithelial cells, cancer-associated fibroblasts, blood vessels, lymphatic vessels, and nerves. In this review, we discuss the mechanistic consequences of Adora2b activation on cell types in the tumor microenvironment. As the cell-autonomous role of adenosine signaling through Adora2b has not been comprehensively studied in pancreatic cancer cells, we will also discuss published data from other malignancies to infer emerging therapeutic considerations for targeting the Adora2b adenosine receptor to reduce the proliferative, invasive, and metastatic potential of PDAC cells.
AB - Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense desmoplastic stroma that impedes drug delivery, reduces parenchymal blood flow, and suppresses the anti-tumor immune response. The extracellular matrix and abundance of stromal cells result in severe hypoxia within the tumor microenvironment (TME), and emerging publications evaluating PDAC tumorigenesis have shown the adenosine signaling pathway promotes an immunosuppressive TME and contributes to the overall low survival rate. Hypoxia increases many elements of the adenosine signaling pathway, resulting in higher adenosine levels in the TME, further contributing to immune suppression. Extracellular adenosine signals through 4 adenosine receptors (Adora1, Adora2a, Adora2b, Adora3). Of the 4 receptors, Adora2b has the lowest affinity for adenosine and thus, has important consequences when stimulated by adenosine binding in the hypoxic TME. We and others have shown that Adora2b is present in normal pancreas tissue, and in injured or diseased pancreatic tissue, Adora2b levels are significantly elevated. The Adora2b receptor is present on many immune cells, including macrophages, dendritic cells, natural killer cells, natural killer T cells, γδ T cells, B cells, T cells, CD4+ T cells, and CD8+ T cells. In these immune cell types, adenosine signaling through Adora2b can reduce the adaptive anti-tumor response, augmenting immune suppression, or may contribute to transformation and changes in fibrosis, perineural invasion, or the vasculature by binding the Adora2b receptor on neoplastic epithelial cells, cancer-associated fibroblasts, blood vessels, lymphatic vessels, and nerves. In this review, we discuss the mechanistic consequences of Adora2b activation on cell types in the tumor microenvironment. As the cell-autonomous role of adenosine signaling through Adora2b has not been comprehensively studied in pancreatic cancer cells, we will also discuss published data from other malignancies to infer emerging therapeutic considerations for targeting the Adora2b adenosine receptor to reduce the proliferative, invasive, and metastatic potential of PDAC cells.
KW - Adenosine receptor 2B
KW - CD8+ T cell response
KW - hypoxia
KW - immunotherapy
KW - pancreatic adenocarcinoma
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U2 - 10.3389/fimmu.2023.1163585
DO - 10.3389/fimmu.2023.1163585
M3 - Review article
C2 - 37187740
AN - SCOPUS:85159156811
SN - 1664-3224
VL - 14
JO - Frontiers in immunology
JF - Frontiers in immunology
M1 - 1163585
ER -