bims-meluca 2022-11-13 papers

Front Immunol. 2022 ;13 1003581

Prognostic value of hematologic parameters in advanced non-small cell lung cancer patients receiving anti-PD-1 inhibitors.

Xinmin Zhao, Xianghua Wu, Hui Yu, Huijie Wang, Si Sun, Zhihuang Hu, Cuicui Liu, Junli Zhang, Yang Shao, Jialei Wang.

Background: The association between hematologic parameters and anti-programmed death-1 (PD-1) inhibitors was generally examined without considering therapy lines and medicine types. The study was aimed to identify potential hematologic biomarkers associated with clinical outcome in patients with non-small cell lung cancer (NSCLC) treated with first-line pembrolizumab and subsequent-line nivolumab.Materials and methods: 161 NSCLC patients were categorized into first-line pembrolizumab group (pembrolizumab group) and subsequent-line nivolumab group (nivolumab group). Univariate and multivariate Cox regression analyses were used to evaluate the prognostic value of hematologic parameters for clinical outcomes.
Results: The median progression-free survival (mPFS) was 9.6 months in the pembrolizumab group and 4.1 months in the nivolumab group (HR =1.61; P = 0.012); the median overall survival (mOS) was not reached in the pembrolizumab group and 17.7 months in the nivolumab group (HR =1.37; P = 0.23). Of the 79 patients in the pembrolizumab group, baseline PD-L1 tumor proportion score (TPS)≥1% was an independent factor of longer PFS and OS. Age≥60 years, absolute platelet count (APC)≥220×10<sup>9</sup>/L and platelet-to-lymphocyte ratio (PLR)≥120 were associated with inferior PFS. Of the 82 patients in the nivolumab group, absolute neutrophil count (ANC)≥3×10<sup>9</sup>/L was associated with longer PFS, while LDH (lactate dehydrogenase)≥160 U/L was associated with inferior PFS and derived neutrophil-to-lymphocyte ratio (dNLR)≥1.2 was associated with longer OS.
Conclusion: Our study identified multiple clinically accessible prognostic biomarkers in the peripheral blood in both the pembrolizumab and nivolumab subgroups.

Keywords: NSCLC; first-line pembrolizumab; hematologic parameters; nivolumab; prognosis; subsequent-line

DOI: https://doi.org/10.3389/fimmu.2022.1003581

Front Genet. 2022 ;13 1016085

Peripheral blood markers predict immunotherapeutic efficacy in patients with advanced non-small cell lung cancer: A multicenter study.

Shuai Liu, Liuyuan Zhao, Guohua Zhou.

This study aims to investigate the prognostic impact of peripheral blood markers in patients with advanced non-small cell lung cancer (NSCLC) undergoing immunotherapy. In the current multicenter study, 157 advanced NSCLC cases treated by immunotherapy at three institutions were included. Biochemical parameters in baseline peripheral blood were collected. The associations between biochemical parameters and prognosis were investigated by the Kaplan-Meier survival analyses and Cox regression, and the predictive performances of biomarkers were evaluated via receiver operating characteristic analysis. The neutrophil-to-lymphocyte ratio (NLR) (progression-free survival [PFS]: hazard ratio [HR], 1.766; 95% confidence interval [CI], 1.311-2.380; p < 0.001; overall survival [OS]: HR, 1.283; 95% CI, 1.120-1.469; p < 0.001) and red blood cell distribution width (RDW) (PFS: HR, 1.052; 95% CI, 1.005-1.102; p = 0.031; OS: HR, 1.044; 95% CI, 1.001-1.091; p = 0.042) were revealed as independent predictors for both PFS and OS. In addition, NLR ≥3.79 (1-year PFS, 24.2% [95% CI, 15.2%-38.4%] versus 27.3% [95% CI, 18.2%-41.1%], p = 0.041; 1-year OS, 44.2% [95% CI, 32.5%-60.1%] versus 71.8% [95% CI, 60.6%-85.2%], p < 0.001) or RDW ≥44.8 g/L (1-year PFS, 19.2% [95% CI, 11.4%-32.3%] versus 31.7% [95% CI, 21.9%-46.0%], p = 0.049; 1-year OS, 54.0% [95% CI, 42.7%-68.3%] versus 63.1% [95% CI, 50.6%-78.6%], p = 0.014) was significantly correlated to poorer PFS and OS than NLR < 3.79 or RDW <44.8 g/L. Moreover, NLR and RDW achieved areas under the curve with 0.651 (95% CI, 0.559-0.743) and 0.626 (95% CI, 0.520-0.732) for predicting PFS, and 0.660 (95% CI, 0.567-0.754) and 0.645 (95% CI, 0.552-0.739), for OS. Therefore, PLR and RDW could help predict the immunotherapeutic efficacy of advanced NSCLC.

Keywords: biomarker; neutrophil-to-lymphocyte ratio; non-small cell lung cancer; peripheral blood; red blood cell distribution width

DOI: https://doi.org/10.3389/fgene.2022.1016085

Cancers (Basel). 2022 Oct 25. pii: 5233. [Epub ahead of print]14(21):

The RSL3 Induction of KLK Lung Adenocarcinoma Cell Ferroptosis by Inhibition of USP11 Activity and the NRF2-GSH Axis.

Wenlong Zhang, Xiaohe Li, Jiaqian Xu, Ying Wang, Zhengcao Xing, Shuming Hu, Qiuju Fan, Shaoyong Lu, Jinke Cheng, Jianmin Gu, Rong Cai.

Antioxidant transcription factor NRF2 plays a pivotal role in cell ferroptosis. KLK lung adenocarcinoma (LUAD) is a specific molecular subtype of Kras-mutant LUAD. The activation of mutant Kras in combination with the inactivation of Lkb1 and Keap1 abnormally increases NRF2 expression, while high NRF2 confers KLK LUAD cell resistance to ferroptosis. This study assessed the inhibition of NRF2-GSH axis to sensitize a small molecule RSL3 to induce KLK LUAD cell ferroptosis and then explored the underlying molecular mechanisms. The data showed that the NRF2-GSH inhibition sensitized RSL3 induction of KLK LUAD cell ferroptosis in vitro, while RSL3 treatment reduced level of NRF2 protein in KLK LUAD during ferroptosis. Moreover, RSL3 treatment inhibited activity of the NRF2-GSH signaling during in KLK LUAD cell ferroptosis in vitro and in vivo. Mechanistically, the RSL3 reduction of NRF2 expression was through the promotion of NRF2 ubiquitination in KLK LUAD cells. In addition, RSL3 was able to directly bind to USP11, a recently identified de-ubiquitinase of NRF2, and inactivate USP11 protein to induce NRF2 protein ubiquitination and degradation in KLK LUAD cells. These data revealed a novel mechanism of RSL3 induction in KLK LUAD cell ferroptosis by suppression of the USP11-NRF2-GSH signaling. Future study will confirm RSL3 as a novel therapeutic approach in control of KLK lung adenocarcinoma.

Keywords: KLK LUAD; NRF2; RSL3; USP11; ferroptosis

DOI: https://doi.org/10.3390/cancers14215233

Cells. 2022 Oct 25. pii: 3371. [Epub ahead of print]11(21):

Lianxiang Luo, Zhentao Zhang, Yanmin Weng, Jiayan Zeng.

Ferroptosis, a newly discovered iron-dependent type of cell death, has been found to play a crucial role in the depression of tumorigenesis. However, the prognostic value of ferroptosis-related genes (FRGs) in lung adenocarcinoma (LUAD) remains to be further elucidated. Differential expression analysis and univariate Cox regression analysis were utilized in this study to search for FRGs that were associated with the prognosis of LUAD patients. The influences of candidate markers on LUAD cell proliferation, migration, and ferroptosis were evaluated by CCK8, colony formation, and functional experimental assays in association with ferroptosis. To predict the prognosis of LUAD patients, we constructed a predictive signature comprised of six FRGs. We discovered a critical gene (GCLC) after intersecting the prognostic analysis results of all aspects, and its high expression was associated with a bad prognosis in LUAD. Correlation research revealed that GCLC was related to a variety of clinical information from LUAD patients. At the same time, in the experimental verification, we found that GCLC expression was upregulated in LUAD cell lines, and silencing GCLC accelerated ferroptosis and decreased LUAD cell proliferation and invasion. Taken together, this study established a novel ferroptosis-related gene signature and discovered a crucial gene, GCLC, that might be a new prognostic biomarker of LUAD patients, as well as provide a potential therapeutic target for LUAD patients.

Keywords: GCLC; ferroptosis; lung adenocarcinoma; overall survival; prognostic signature

DOI: https://doi.org/10.3390/cells11213371

Cancers (Basel). 2022 Oct 22. pii: 5191. [Epub ahead of print]14(21):

Both In Situ and Circulating SLC3A2 Could Be Used as Prognostic Markers for Human Lung Squamous Cell Carcinoma and Lung Adenocarcinoma.

Dahua Liu, Min An, Guimin Wen, Yanan Xing, Pu Xia.

SLC3A2, the heavy chain of the CD98 protein, is highly expressed in many cancers, including lung cancer. It can regulate the proliferation and the metastasis of cancer cells via the integrin signaling pathway. Liquid biopsy is a novel method for tumor diagnosis. The diagnostic or prognostic roles of serum SLC3A2 in lung cancer are still not clear. In this study, we analyzed SLC3A2 mRNA levels in human lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD) using the TCGA database and serum SLC3A2 protein levels using ELISA. We confirmed high SLC3A2 levels in both the serum and tissue of LUAD and LUSC patients. Both serum and tissue SLC3A2 could be used as prognostic markers for overall LUAD and subgroups of LUSC patients. SLC3A2 induced tumorigenesis via the MEK/ERK signaling pathway in LUAD and LUSC cells.

Keywords: MEK/ERK pathway; SLC3A2; lung adenocarcinoma; lung squamous cell carcinoma; prognosis

DOI: https://doi.org/10.3390/cancers14215191

Cancers (Basel). 2022 Nov 02. pii: 5405. [Epub ahead of print]14(21):

Cancer Cachexia among Patients with Advanced Non-Small-Cell Lung Cancer on Immunotherapy: An Observational Study with Exploratory Gut Microbiota Analysis.

Taiki Hakozaki, Alexis Nolin-Lapalme, Masato Kogawa, Yusuke Okuma, Shohei Nakamura, Danielle Moreau-Amaru, Taichi Tamura, Yukio Hosomi, Haruko Takeyama, Corentin Richard, Masahito Hosokawa, Bertrand Routy.

Cancer cachexia exerts a negative clinical influence on patients with advanced non-small-cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICI). The prognostic impact of body weight change during ICI treatment remains unknown. The gut microbiota (GM) is a key contributor to the response to ICI therapy in cancer patients. However, the association between cancer cachexia and GM and their association with the response to ICIs remains unexplored. This study examined the association of cancer cachexia with GM composition and assessed the impact of GM on clinical outcomes in patients with NSCLC treated with ICIs. In this observational, prospective study, which included 113 Japanese patients with advanced NSCLC treated with ICIs, the prevalence of cachexia was 50.4% (57/113). The median progression-free survival (PFS) and overall survival (OS) were significantly shorter in the cachexia group than in the non-cachexia group (4.3 vs. 11.6 months (p = 0.003) and 12.0 months vs. not reached (p = 0.02), respectively). A multivariable analysis revealed that baseline cachexia was independently associated with a shorter PFS. Moreover, a gain in body weight from the baseline (reversible cachexia) was associated with a significantly longer PFS and OS compared to irreversible cachexia. Microbiome profiling with 16S rRNA analysis revealed that the cachexia group presented an overrepresentation of the commensal bacteria, Escherichia-Shigella and Hungatella, while the non-cachexia group had a preponderance of Anaerostipes,&nbsp;Blautia, and Eubacterium ventriosum. Anaerostipes and E. ventriosum were associated with longer PFS and OS. Moreover, a cachexia status correlated with the systemic inflammatory marker-derived-neutrophil-to-lymphocytes ratio (dNLR) and Lung Immune Prognostic Index (LIPI) indexes. Our study demonstrates that cachexia and longitudinal bodyweight change have a prognostic impact on patients with advanced NSCLC treated with ICI therapy. Moreover, our study demonstrates that bacteria associated with ICI resistance are also linked to cachexia. Targeted microbiota interventions may represent a new type of treatment to overcome cachexia in patients with NSCLC.

Keywords: biomarker; cancer cachexia; gut microbiota; immunotherapy; non-small-cell lung cancer; prognosis

DOI: https://doi.org/10.3390/cancers14215405