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

Abstract

BackgroundThe 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.MethodsUsing 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.ResultsElevated 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.ConclusionGPX2 overexpression represents a novel potentially targetable effector of immune escape in cold tumors.

Targeted proteomic quantitation of NRF2 signaling and predictive biomarkers in HNSCC

“…Our data also present several unexpected observations pertaining to NRF2 driven immune-suppression, a correlation between the NRF2 and SOX2 oncogenes, and NRF2 activation in an HPV(+) background. First, given recent publications, we expected NRF2 activation to inversely correlate with T-cell infiltration [23, 32, 33]. Our data do not support this hypothesis.…”

Dysregulation and Epigenetic Reprogramming of NRF2 Signaling Axis Promote Acquisition of Cisplatin Resistance and Metastasis in Head and Neck Squamous Cell Carcinoma

“…S3B), the TP53 status alone was a poor prognosticator of OS. Using our previously published and validated NRF2 gene signature ( 40 ), however, we found that OCSCC patients with a high NRF2 activation score had significantly worse OS compared with those with low NRF2 scores (Supplementary Fig. S3C; MS = 35.5 months vs. 65.8 months; P = 0.038).…”

“…Focusing on the OCSCC (Supplementary Figure S3B), the TP53 status alone was a poor prognosticator of overall survival (OS). Using our previously published and validated NRF2 gene signature (40), however, we found that OCSCC patients with a high NRF2 activation score had significantly worse OS compared to those with low NRF2 scores (Supplementary Figure S3C, MS = 35.5 months vs 65.8 months, P =0.038). A similar trend of worse survival was found if patient were instead stratified by mutations in the NRF2 pathway, but it didn't reach statistical significance (Supplementary Figure S3D).…”

Identification of the molecular characteristics associated with microsatellite status of colorectal cancer patients for the clinical application of immunotherapy

“…In addition, it is noteworthy that some of these 29 specific single-cell marker genes have been studied in tumor immunotherapy( Macor et al, 2015 ; Strati et al, 2017 ; Shen et al, 2021 ; Ahmed et al, 2022 ; Min et al, 2022 ), but their role in the response of CRC to immunotherapy is still unclear. Combined with the results of CellMiner, it is suggested that these genes may be potential synergistic targets for enhancing the sensitivity of immunotherapy in CRC patients.…”