bims-meluca 2022-08-28 papers

J Immunother Cancer. 2022 Aug;pii: e004752. [Epub ahead of print]10(8):

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

Kazi Mokim Ahmed, Ratna Veeramachaneni, Defeng Deng, Nagireddy Putluri, Vasanta Putluri, Maria F Cardenas, David A Wheeler, William K Decker, Andy I Frederick, Sawad Kazi, Andrew G Sikora, Vlad C Sandulache, Mitchell J Frederick.

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.

Keywords: head and neck neoplasms; immune evation; immune tolerance; immunotherapy; tumor escape

DOI: https://doi.org/10.1136/jitc-2022-004752

Heliyon. 2022 Aug;8(8): e10164

A novel metabolic-immune related signature predicts prognosis and immunotherapy response in lung adenocarcinoma.

Xiaolong Tang, Chumei Qi, Honghong Zhou, Yongshuo Liu.

Background: Lung adenocarcinoma (LUAD) is one of the most frequent types of lung cancer, with a high mortality and recurrence rate. This study aimed to design a RiskScore to predict the prognosis and immunotherapy response of LUAD patients due to a lack of metabolic and immune-related prognostic models.Methods: To identify prognostic genes and generate a RiskScore, we conducted differential gene expression analysis, bulk survival analysis, Lasso regression analysis, and univariate and multivariate Cox regression analysis using TCGA-LUAD as a training subset. GSE31210 and GSE50081 were used as validation subsets to validate the constructed RiskScore. Following that, we explored the connection between RiskScore and clinicopathological characteristics, immune cells infiltration, and immunotherapy. In addition, we investigated into RiskScore's biological roles and constructed a Nomogram model.
Results: A RiskScore was identified consisting of five genes (DKK1, CCL20, NPAS2, GNPNAT1 and MELTF). In the RiskScore-high group, LUAD patients showed decreased overall survival rates and shorter progression-free survival. Multiple clinicopathological characteristics and immune cells infiltration in TME, in particular, have been linked to RiskScore. Of note, RiskScore-related genes have been implicated to substance metabolism, carcinogenesis, and immunological pathways, among other things. Finally, the C-index of the RiskScore-based Nomogram model was 0.804 (95% CI: 0.783-0.825), and time-dependent ROC predicted probabilities of 1-, 3- and 5-year survival for LUAD patients were 0.850, 0.848 and 0.825, respectively.
Conclusion: The RiskScore, which integrated metabolic and immunological features with DKK1, CCL20, NPAS2, GNPNAT1, and MELTF, could reliably predict prognosis and immunotherapy response in LUAD patients. Moreover, the RiskScore-based Nomogram model had a promising clinical application.

Keywords: CCL20; DKK1; GNPNAT1; Lung adenocarcinoma; MELTF; NPAS2; Prognostic; Tumor immunity

DOI: https://doi.org/10.1016/j.heliyon.2022.e10164

Int J Mol Sci. 2022 Aug 09. pii: 8863. [Epub ahead of print]23(16):

Anti-Angiogenic Therapy in ALK Rearranged Non-Small Cell Lung Cancer (NSCLC).

Aaron C Tan, Nick Pavlakis.

The management of advanced lung cancer has been transformed with the identification of targetable oncogenic driver alterations. This includes anaplastic lymphoma kinase (ALK) gene rearrangements. ALK tyrosine kinase inhibitors (TKI) are established first-line treatment options in advanced ALK rearranged non-small cell lung cancer (NSCLC), with several next-generation ALK TKIs (alectinib, brigatinib, ensartinib and lorlatinib) demonstrating survival benefit compared with the first-generation ALK TKI crizotinib. Still, despite high objective response rates and durable progression-free survival, drug resistance inevitably ensues, and treatment options beyond ALK TKI are predominantly limited to cytotoxic chemotherapy. Anti-angiogenic therapy targeting the vascular endothelial growth factor (VEGF) signaling pathway has shown efficacy in combination with platinum-doublet chemotherapy in advanced NSCLC without a driver alteration, and with EGFR TKI in advanced EGFR mutated NSCLC. The role for anti-angiogenic therapy in ALK rearranged NSCLC, however, remains to be elucidated. This review will discuss the pre-clinical rationale, clinical trial evidence to date, and future directions to evaluate anti-angiogenic therapy in ALK rearranged NSCLC.

Keywords: ALK rearrangement; anaplastic lymphoma kinase; anti-angiogenesis; non-small cell lung cancer; vascular endothelial growth factor

DOI: https://doi.org/10.3390/ijms23168863

Int J Mol Sci. 2022 Aug 15. pii: 9134. [Epub ahead of print]23(16):

Metformin Mitigated Obesity-Driven Cancer Aggressiveness in Tumor-Bearing Mice.

Chun-Jung Chen, Chih-Cheng Wu, Cheng-Yi Chang, Jian-Ri Li, Yen-Chuan Ou, Wen-Ying Chen, Su-Lan Liao, Jiaan-Der Wang.

Metformin may offer benefits to certain cancer populations experiencing metabolic abnormalities. To extend the anticancer studies of metformin, a tumor model was established through the implantation of murine Lewis Lung Carcinoma (LLC) cells to Normal Diet (ND)-fed and High-Fat Diet (HFD)-fed C57BL/6 mice. The HFD-fed mice displayed metabolic and pro-inflammatory alterations together with accompanying aggressive tumor growth. Metformin mitigated tumor growth in HFD-fed mice, paralleled by reductions in circulating glucose, insulin, soluble P-selectin, TGF-β1 and High Mobility Group Box-1 (HMGB1), as well as tumor expression of cell proliferation, aerobic glycolysis, glutaminolysis, platelets and neutrophils molecules. The suppressive effects of metformin on cell proliferation, migration and oncogenic signaling molecules were confirmed in cell study. Moreover, tumor-bearing HFD-fed mice had higher contents of circulating and tumor immunopositivity of Neutrophil Extracellular Traps (NETs)-associated molecules, with a suppressive effect from metformin. Data taken from neutrophil studies confirmed the inhibitory effect that metformin has on NET formation induced by HMGB1. Furthermore, HMGB1 was identified as a promoting molecule to boost the transition process towards NETs. The current study shows that metabolic, pro-inflammatory and NET alterations appear to play roles in the obesity-driven aggressiveness of cancer, while also representing candidate targets for anticancer potential of metformin.

Keywords: metabolism; metformin; neutrophil extracellular traps; neutrophils; obesity; salignancy

DOI: https://doi.org/10.3390/ijms23169134