A2AR Expression and Immunosuppressive Environment Independent of <i>KRAS</i> and <i>GNAS</i> Mutations in Pseudomyxoma Peritonei

In pseudomyxoma peritonei (PMP), <i>KRAS</i> and <i>GNAS</i> mutations are frequent. We hypothesized that these mutations may contribute to the suppression of antitumor immunity: <i>KRAS</i> may induce GMCSF expression, while <i>GNAS</i> may enhance th...

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Main Authors: Shigeki Kusamura, Adele Busico, Elena Conca, Iolanda Capone, Luca Agnelli, Daniele Lorenzini, Silvia Brich, Marta Angelini, Chiara Costanza Volpi, Desirè Viola Trupia, Vincenzo Lagano, Tommaso Torelli, Annunziata Gloghini, Dario Baratti, Marcello Guaglio, Massimo Milione, Marcello Deraco, Federica Perrone
Format: Article
Language:English
Published: MDPI AG 2023-07-01
Series:Biomedicines
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Online Access:https://www.mdpi.com/2227-9059/11/7/2049
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author Shigeki Kusamura
Adele Busico
Elena Conca
Iolanda Capone
Luca Agnelli
Daniele Lorenzini
Silvia Brich
Marta Angelini
Chiara Costanza Volpi
Desirè Viola Trupia
Vincenzo Lagano
Tommaso Torelli
Annunziata Gloghini
Dario Baratti
Marcello Guaglio
Massimo Milione
Marcello Deraco
Federica Perrone
author_facet Shigeki Kusamura
Adele Busico
Elena Conca
Iolanda Capone
Luca Agnelli
Daniele Lorenzini
Silvia Brich
Marta Angelini
Chiara Costanza Volpi
Desirè Viola Trupia
Vincenzo Lagano
Tommaso Torelli
Annunziata Gloghini
Dario Baratti
Marcello Guaglio
Massimo Milione
Marcello Deraco
Federica Perrone
author_sort Shigeki Kusamura
collection DOAJ
description In pseudomyxoma peritonei (PMP), <i>KRAS</i> and <i>GNAS</i> mutations are frequent. We hypothesized that these mutations may contribute to the suppression of antitumor immunity: <i>KRAS</i> may induce GMCSF expression, while <i>GNAS</i> may enhance the expression of cyclic adenosine monophosphate and A2AR signaling. This study aimed to explore possible mechanisms facilitated by <i>KRAS</i> and <i>GNAS</i> mutations for escaping immune surveillance. Additionally, we looked for new potential therapeutic and prognostic targets in this rare disease which is poorly characterized at the molecular level. GM-CSF, A2AR, CD73, CD39, and PD-L1 expression was investigated by immunohistochemistry in 40 PMPs characterized for <i>GNAS</i> and <i>KRAS</i> mutational status. Immune cell populations were studied by immunohistochemistry and nanostring nCounter<sup>®</sup>. Following the criteria of a prognostic nomogram reported for PMP, we stratified the patients into two different risk groups, with 28 “low-risk” and 12 “high-risk” patients. We observed the expression of GM-CSF (74%); CD39 (37%); CD73 (53%); A2AR (74%); and PD-L1 (16%) which was unrelated to <i>GNAS</i> or <i>KRAS</i> status. The tumor microenvironment showed the presence of CD4+ T cells (86%); CD8+ T cells (27%); CD20+ B (67%); CD15+ cells (86%); and CD163+ M2 macrophages (67%), while CD56+ NK cells were absent. CD163 expression (27%) in PMP tumor cells was associated with poor prognosis. <i>GNAS</i> mutation and A2AR expression were not associated with a specific immune transcriptional signature. However, the expression assay revealed 21 genes associated with prognosis. The “high-risk” patients exhibited worse progression-free survival (HR = 2.3, CI 95%: 1.1–5.1, <i>p</i> = 0.034) and significant downregulation of <i>MET</i>, <i>IL8</i>, <i>PPARG</i>, <i>DTX4</i>, <i>HMGA1, ZIC2</i>, <i>WNT5B,</i> and <i>CCRL2</i>. In conclusion, we documented the presence of immunosuppressive factors such as GM-CSF, A2AR, and PD-L1 in PMP. These factors were not associated with <i>GNAS</i> and <i>KRAS</i> status and could be explored as therapeutic molecular targets. Additionally, a set of potential prognostic biomarkers, including CD163 expression in tumor cells, deserve further investigation.
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spelling doaj.art-bcdd95d8ae5e422d8150f874928f4e692023-11-18T18:28:44ZengMDPI AGBiomedicines2227-90592023-07-01117204910.3390/biomedicines11072049A2AR Expression and Immunosuppressive Environment Independent of <i>KRAS</i> and <i>GNAS</i> Mutations in Pseudomyxoma PeritoneiShigeki Kusamura0Adele Busico1Elena Conca2Iolanda Capone3Luca Agnelli4Daniele Lorenzini5Silvia Brich6Marta Angelini7Chiara Costanza Volpi8Desirè Viola Trupia9Vincenzo Lagano10Tommaso Torelli11Annunziata Gloghini12Dario Baratti13Marcello Guaglio14Massimo Milione15Marcello Deraco16Federica Perrone17Peritoneal Surface Malignancy Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, ItalyLaboratory of Diagnostic and Molecular Research, Department of Diagnostic Innovation, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, ItalyLaboratory of Diagnostic and Molecular Research, Department of Diagnostic Innovation, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, ItalyLaboratory of Diagnostic and Molecular Research, Department of Diagnostic Innovation, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, ItalyLaboratory of Diagnostic and Molecular Research, Department of Diagnostic Innovation, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, ItalyLaboratory of Diagnostic and Molecular Research, Department of Diagnostic Innovation, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, ItalyLaboratory of Diagnostic and Molecular Research, Department of Diagnostic Innovation, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, ItalyLaboratory of Diagnostic and Molecular Research, Department of Diagnostic Innovation, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, ItalyLaboratory of Diagnostic and Molecular Research, Department of Diagnostic Innovation, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, ItalyLaboratory of Diagnostic and Molecular Research, Department of Diagnostic Innovation, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy1st Pathology Division, Department of Diagnostic Innovation, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, ItalyLaboratory of Diagnostic and Molecular Research, Department of Diagnostic Innovation, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, ItalyLaboratory of Diagnostic and Molecular Research, Department of Diagnostic Innovation, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, ItalyPeritoneal Surface Malignancy Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, ItalyPeritoneal Surface Malignancy Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy1st Pathology Division, Department of Diagnostic Innovation, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, ItalyPeritoneal Surface Malignancy Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, ItalyLaboratory of Diagnostic and Molecular Research, Department of Diagnostic Innovation, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, ItalyIn pseudomyxoma peritonei (PMP), <i>KRAS</i> and <i>GNAS</i> mutations are frequent. We hypothesized that these mutations may contribute to the suppression of antitumor immunity: <i>KRAS</i> may induce GMCSF expression, while <i>GNAS</i> may enhance the expression of cyclic adenosine monophosphate and A2AR signaling. This study aimed to explore possible mechanisms facilitated by <i>KRAS</i> and <i>GNAS</i> mutations for escaping immune surveillance. Additionally, we looked for new potential therapeutic and prognostic targets in this rare disease which is poorly characterized at the molecular level. GM-CSF, A2AR, CD73, CD39, and PD-L1 expression was investigated by immunohistochemistry in 40 PMPs characterized for <i>GNAS</i> and <i>KRAS</i> mutational status. Immune cell populations were studied by immunohistochemistry and nanostring nCounter<sup>®</sup>. Following the criteria of a prognostic nomogram reported for PMP, we stratified the patients into two different risk groups, with 28 “low-risk” and 12 “high-risk” patients. We observed the expression of GM-CSF (74%); CD39 (37%); CD73 (53%); A2AR (74%); and PD-L1 (16%) which was unrelated to <i>GNAS</i> or <i>KRAS</i> status. The tumor microenvironment showed the presence of CD4+ T cells (86%); CD8+ T cells (27%); CD20+ B (67%); CD15+ cells (86%); and CD163+ M2 macrophages (67%), while CD56+ NK cells were absent. CD163 expression (27%) in PMP tumor cells was associated with poor prognosis. <i>GNAS</i> mutation and A2AR expression were not associated with a specific immune transcriptional signature. However, the expression assay revealed 21 genes associated with prognosis. The “high-risk” patients exhibited worse progression-free survival (HR = 2.3, CI 95%: 1.1–5.1, <i>p</i> = 0.034) and significant downregulation of <i>MET</i>, <i>IL8</i>, <i>PPARG</i>, <i>DTX4</i>, <i>HMGA1, ZIC2</i>, <i>WNT5B,</i> and <i>CCRL2</i>. In conclusion, we documented the presence of immunosuppressive factors such as GM-CSF, A2AR, and PD-L1 in PMP. These factors were not associated with <i>GNAS</i> and <i>KRAS</i> status and could be explored as therapeutic molecular targets. Additionally, a set of potential prognostic biomarkers, including CD163 expression in tumor cells, deserve further investigation.https://www.mdpi.com/2227-9059/11/7/2049pseudomyxoma peritoneiA2ARCD39CD73PDL-1
spellingShingle Shigeki Kusamura
Adele Busico
Elena Conca
Iolanda Capone
Luca Agnelli
Daniele Lorenzini
Silvia Brich
Marta Angelini
Chiara Costanza Volpi
Desirè Viola Trupia
Vincenzo Lagano
Tommaso Torelli
Annunziata Gloghini
Dario Baratti
Marcello Guaglio
Massimo Milione
Marcello Deraco
Federica Perrone
A2AR Expression and Immunosuppressive Environment Independent of <i>KRAS</i> and <i>GNAS</i> Mutations in Pseudomyxoma Peritonei
Biomedicines
pseudomyxoma peritonei
A2AR
CD39
CD73
PDL-1
title A2AR Expression and Immunosuppressive Environment Independent of <i>KRAS</i> and <i>GNAS</i> Mutations in Pseudomyxoma Peritonei
title_full A2AR Expression and Immunosuppressive Environment Independent of <i>KRAS</i> and <i>GNAS</i> Mutations in Pseudomyxoma Peritonei
title_fullStr A2AR Expression and Immunosuppressive Environment Independent of <i>KRAS</i> and <i>GNAS</i> Mutations in Pseudomyxoma Peritonei
title_full_unstemmed A2AR Expression and Immunosuppressive Environment Independent of <i>KRAS</i> and <i>GNAS</i> Mutations in Pseudomyxoma Peritonei
title_short A2AR Expression and Immunosuppressive Environment Independent of <i>KRAS</i> and <i>GNAS</i> Mutations in Pseudomyxoma Peritonei
title_sort a2ar expression and immunosuppressive environment independent of i kras i and i gnas i mutations in pseudomyxoma peritonei
topic pseudomyxoma peritonei
A2AR
CD39
CD73
PDL-1
url https://www.mdpi.com/2227-9059/11/7/2049
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