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Glutathione peroxidase 2 is a metabolic driver of the tumor immune microenvironment and immune checkpoint inhibitor response

BACKGROUND: The existence of immunologically ‘cold tumors’ frequently found across a wide spectrum of tumor types represents a significant challenge for cancer immunotherapy. Cold tumors have poor baseline pan-leukocyte infiltration, including a low prevalence of cytotoxic lymphocytes, and not surpr...

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Autores principales: Ahmed, Kazi Mokim, Veeramachaneni, Ratna, Deng, Defeng, Putluri, Nagireddy, Putluri, Vasanta, Cardenas, Maria F, Wheeler, David A, Decker, William K, Frederick, Andy I, Kazi, Sawad, Sikora, Andrew G, Sandulache, Vlad C, Frederick, Mitchell J
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BMJ Publishing Group 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9413193/
https://www.ncbi.nlm.nih.gov/pubmed/36002187
http://dx.doi.org/10.1136/jitc-2022-004752
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author Ahmed, Kazi Mokim
Veeramachaneni, Ratna
Deng, Defeng
Putluri, Nagireddy
Putluri, Vasanta
Cardenas, Maria F
Wheeler, David A
Decker, William K
Frederick, Andy I
Kazi, Sawad
Sikora, Andrew G
Sandulache, Vlad C
Frederick, Mitchell J
author_facet Ahmed, Kazi Mokim
Veeramachaneni, Ratna
Deng, Defeng
Putluri, Nagireddy
Putluri, Vasanta
Cardenas, Maria F
Wheeler, David A
Decker, William K
Frederick, Andy I
Kazi, Sawad
Sikora, Andrew G
Sandulache, Vlad C
Frederick, Mitchell J
author_sort Ahmed, Kazi Mokim
collection PubMed
description BACKGROUND: The existence of immunologically ‘cold tumors’ frequently found across a wide spectrum of tumor types represents a significant challenge for cancer immunotherapy. Cold tumors have poor baseline pan-leukocyte infiltration, including a low prevalence of cytotoxic lymphocytes, and not surprisingly respond unfavorably to immune checkpoint (IC) inhibitors. We hypothesized that cold tumors harbor a mechanism of immune escape upstream and independent of ICs that may be driven by tumor biology rather than differences in mutational neoantigen burden. METHODS: Using a bioinformatic approach to analyze TCGA (The Cancer Genome Atlas) RNA sequencing data we identified genes upregulated in cold versus hot tumors across four different smoking-related cancers, including squamous carcinomas from the oral cavity (OCSCC) and lung (LUSC), and adenocarcinomas of the bladder (BLCA) and lung (LUAD). Biological significance of the gene most robustly associated with a cold tumor phenotype across all four tumor types, glutathione peroxidase 2 (GPX2), was further evaluated using a combination of in silico analyses and functional genomic experiments performed both in vitro and in in vivo with preclinical models of oral cancer. RESULTS: Elevated RNA expression of five metabolic enzymes including GPX2, aldo-keto reductase family 1 members AKR1C1, AKR1C3, and cytochrome monoxygenases (CP4F11 and CYP4F3) co-occurred in cold tumors across all four smoking-related cancers. These genes have all been linked to negative regulation of arachidonic acid metabolism—a well-established inflammatory pathway—and are also known downstream targets of the redox sensitive Nrf2 transcription factor pathway. In OCSCC, LUSC, and LUAD, GPX2 expression was highly correlated with Nrf2 activation signatures, also elevated in cold tumors. In BLCA, however, GPX2 correlated more strongly than Nrf2 signatures with decreased infiltration of multiple leukocyte subtypes. GPX2 inversely correlated with expression of multiple pro- inflammatory cytokines/chemokines and NF-kB activation in cell lines and knockdown of GPX2 led to increased secretion of prostaglandin E2 (PGE2) and interleukin-6. Conversely, GPX2 overexpression led to reduced PGE2 production in a murine OCSCC model (MOC1). GPX2 overexpressing MOC1 tumors had a more suppressive tumor immune microenvironment and responded less favorably to anti-cytotoxic T-lymphocytes-associated protein 4 IC therapy in mice. CONCLUSION: GPX2 overexpression represents a novel potentially targetable effector of immune escape in cold tumors.
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spelling pubmed-94131932022-09-12 Glutathione peroxidase 2 is a metabolic driver of the tumor immune microenvironment and immune checkpoint inhibitor response Ahmed, Kazi Mokim Veeramachaneni, Ratna Deng, Defeng Putluri, Nagireddy Putluri, Vasanta Cardenas, Maria F Wheeler, David A Decker, William K Frederick, Andy I Kazi, Sawad Sikora, Andrew G Sandulache, Vlad C Frederick, Mitchell J J Immunother Cancer Basic Tumor Immunology BACKGROUND: The existence of immunologically ‘cold tumors’ frequently found across a wide spectrum of tumor types represents a significant challenge for cancer immunotherapy. Cold tumors have poor baseline pan-leukocyte infiltration, including a low prevalence of cytotoxic lymphocytes, and not surprisingly respond unfavorably to immune checkpoint (IC) inhibitors. We hypothesized that cold tumors harbor a mechanism of immune escape upstream and independent of ICs that may be driven by tumor biology rather than differences in mutational neoantigen burden. METHODS: Using a bioinformatic approach to analyze TCGA (The Cancer Genome Atlas) RNA sequencing data we identified genes upregulated in cold versus hot tumors across four different smoking-related cancers, including squamous carcinomas from the oral cavity (OCSCC) and lung (LUSC), and adenocarcinomas of the bladder (BLCA) and lung (LUAD). Biological significance of the gene most robustly associated with a cold tumor phenotype across all four tumor types, glutathione peroxidase 2 (GPX2), was further evaluated using a combination of in silico analyses and functional genomic experiments performed both in vitro and in in vivo with preclinical models of oral cancer. RESULTS: Elevated RNA expression of five metabolic enzymes including GPX2, aldo-keto reductase family 1 members AKR1C1, AKR1C3, and cytochrome monoxygenases (CP4F11 and CYP4F3) co-occurred in cold tumors across all four smoking-related cancers. These genes have all been linked to negative regulation of arachidonic acid metabolism—a well-established inflammatory pathway—and are also known downstream targets of the redox sensitive Nrf2 transcription factor pathway. In OCSCC, LUSC, and LUAD, GPX2 expression was highly correlated with Nrf2 activation signatures, also elevated in cold tumors. In BLCA, however, GPX2 correlated more strongly than Nrf2 signatures with decreased infiltration of multiple leukocyte subtypes. GPX2 inversely correlated with expression of multiple pro- inflammatory cytokines/chemokines and NF-kB activation in cell lines and knockdown of GPX2 led to increased secretion of prostaglandin E2 (PGE2) and interleukin-6. Conversely, GPX2 overexpression led to reduced PGE2 production in a murine OCSCC model (MOC1). GPX2 overexpressing MOC1 tumors had a more suppressive tumor immune microenvironment and responded less favorably to anti-cytotoxic T-lymphocytes-associated protein 4 IC therapy in mice. CONCLUSION: GPX2 overexpression represents a novel potentially targetable effector of immune escape in cold tumors. BMJ Publishing Group 2022-08-24 /pmc/articles/PMC9413193/ /pubmed/36002187 http://dx.doi.org/10.1136/jitc-2022-004752 Text en © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) .
spellingShingle Basic Tumor Immunology
Ahmed, Kazi Mokim
Veeramachaneni, Ratna
Deng, Defeng
Putluri, Nagireddy
Putluri, Vasanta
Cardenas, Maria F
Wheeler, David A
Decker, William K
Frederick, Andy I
Kazi, Sawad
Sikora, Andrew G
Sandulache, Vlad C
Frederick, Mitchell J
Glutathione peroxidase 2 is a metabolic driver of the tumor immune microenvironment and immune checkpoint inhibitor response
title Glutathione peroxidase 2 is a metabolic driver of the tumor immune microenvironment and immune checkpoint inhibitor response
title_full Glutathione peroxidase 2 is a metabolic driver of the tumor immune microenvironment and immune checkpoint inhibitor response
title_fullStr Glutathione peroxidase 2 is a metabolic driver of the tumor immune microenvironment and immune checkpoint inhibitor response
title_full_unstemmed Glutathione peroxidase 2 is a metabolic driver of the tumor immune microenvironment and immune checkpoint inhibitor response
title_short Glutathione peroxidase 2 is a metabolic driver of the tumor immune microenvironment and immune checkpoint inhibitor response
title_sort glutathione peroxidase 2 is a metabolic driver of the tumor immune microenvironment and immune checkpoint inhibitor response
topic Basic Tumor Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9413193/
https://www.ncbi.nlm.nih.gov/pubmed/36002187
http://dx.doi.org/10.1136/jitc-2022-004752
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