bims-meluca 2023-10-29 papers

BMC Cancer. 2023 Oct 23. 23(1): 1023

Impact of BMI on the survival outcomes of non-small cell lung cancer patients treated with immune checkpoint inhibitors: a meta-analysis.

Tongtong Zhang, Shuluan Li, Jianhua Chang, Yan Qin, Chao Li.

OBJECTIVES: ICIs have become the standard treatment for advanced NSCLC patients. Currently, PD-L1 is the most widely useful biomarker to predict ICI efficacy, but the sensitivity and specificity are limited. Therefore, the useful predictive biomarkers of ICI efficacy is urgently needed. BMI is an internationally used measure of body health. Obesity may affect ICI efficacy by changing T cell functions. This meta-analysis aimed to clarify the relationship between BMI and survival outcomes of NSCLC patients treated with ICIs.METHODS: A systematic review was conducted to identify studies that assessed the association between BMI and survival outcomes in patients treated with ICIs. OS was the primary endpoint, and PFS was the secondary endpoint. Random-effect models or fixed-effect models were utilized to combine study effects according to the Cochran Q and I2 tests.
RESULTS: Nine studies, including 4602 NSCLC patients treated with ICIs, that met the inclusion criteria were selected for this meta-analysis. There was no significant difference in PFS (HR 0.885; 95% CI 0.777-1.009, p = 0.068) or OS (HR 0.947; 95% CI 0.789-1.137, p = 0.560) between the low BMI group and the high BMI group. However, in the subgroup analysis, compared with normal-weight patients, overweight and obese patients achieved prolonged PFS (HR 0.862; 95% CI 0.760-0.978, p = 0.021) and OS (HR 0.818; 95% CI 0.741-0.902, p<0.0001).
CONCLUSION: Overweight and obese NSCLC patients tend to achieve prolonged survival time with ICI regimens. Further prospective studies are needed to strengthen the association between ICI outcomes and BMI levels.

Keywords: BMI; ICIs; NSCLC

DOI: https://doi.org/10.1186/s12885-023-11512-y

bioRxiv. 2023 Oct 09. pii: 2023.10.06.561131. [Epub ahead of print]

G6PD Maintains Redox Homeostasis and Biosynthesis in LKB1-Deficient KRAS-Driven Lung Cancer.

Taijin Lan, Sara Arastu, Samuel Wang, Jarrick Lam, Wenping Wang, Vrushank Bhatt, Eduardo Cararo Lopes, Zhixian Hu, Michael Sun, Xuefei Luo, Jonathan M Ghergurovich, Changlong Li, Xiaoyang Su, Joshua D Rabinowitz, Eileen White, Jessie Yanxiang Guo.

Cancer cells depend on nicotinamide adenine dinucleotide phosphate (NADPH) to combat oxidative stress and support reductive biosynthesis. One major NAPDH production route is the oxidative pentose phosphate pathway (committed step: glucose-6-phosphate dehydrogenase, G6PD). Alternatives exist and can compensate in some tumors. Here, using genetically-engineered lung cancer model, we show that ablation of G6PD significantly suppresses Kras G12D/+ ;Lkb1 -/- (KL) but not Kras G12D/+ ;p53 -/- (KP) lung tumorigenesis. In vivo isotope tracing and metabolomics revealed that G6PD ablation significantly impaired NADPH generation, redox balance and de novo lipogenesis in KL but not KP lung tumors. Mechanistically, in KL tumors, G6PD ablation caused p53 activation that suppressed tumor growth. As tumor progressed, G6PD-deficient KL tumors increased an alternative NADPH source, serine-driven one carbon metabolism, rendering associated tumor-derived cell lines sensitive to serine/glycine depletion. Thus, oncogenic driver mutations determine lung cancer dependence on G6PD, whose targeting is a potential therapeutic strategy for tumors harboring KRAS and LKB1 co-mutations.

DOI: https://doi.org/10.1101/2023.10.06.561131

Cell Rep. 2023 Oct 25. pii: S2211-1247(23)01307-4. [Epub ahead of print]42(11): 113295

KEAP1 mutation in lung adenocarcinoma promotes immune evasion and immunotherapy resistance.

Lung cancer treatment has benefited greatly through advancements in immunotherapies. However, immunotherapy often fails in patients with specific mutations like KEAP1, which are frequently found in lung adenocarcinoma. We established an antigenic lung cancer model and used it to explore how Keap1 mutations remodel the tumor immune microenvironment. Using single-cell technology and depletion studies, we demonstrate that Keap1-mutant tumors diminish dendritic cell and T cell responses driving immunotherapy resistance. This observation was corroborated in patient samples. CRISPR-Cas9-mediated gene targeting revealed that hyperactivation of the NRF2 antioxidant pathway is responsible for diminished immune responses in Keap1-mutant tumors. Importantly, we demonstrate that combining glutaminase inhibition with immune checkpoint blockade can reverse immunosuppression, making Keap1-mutant tumors susceptible to immunotherapy. Our study provides new insight into the role of KEAP1 mutations in immune evasion, paving the way for novel immune-based therapeutic strategies for KEAP1-mutant cancers.

Keywords: CD103 DC; CP: Cancer; CP: Immunology; KEAP1; LUAD; NRF2; NSCLC; T cell; adenocarcinoma; immune surveillance; immunotherapy; lung cancer

DOI: https://doi.org/10.1016/j.celrep.2023.113295

Insights Imaging. 2023 Oct 26. 14(1): 182

Prognostic utility of body composition parameters based on computed tomography analysis of advanced non-small cell lung cancer treated with immune checkpoint inhibitors.

Ji Eun Park, Jaemin Jo, Jeonghwan Youk, Miso Kim, Soon Ho Yoon, Bhumsuk Keam, Tae Min Kim, Dong-Wan Kim.

OBJECTIVE: The purpose of this study was to evaluate the prognostic impact of body composition parameters based on computed tomography (CT) in patients with non-small cell lung cancer (NSCLC) who received ICI treatment.METHODS: This retrospective study analyzed the data from advanced NSCLC patients treated with ICI therapy between 2013 and 2019. We included patients with NSCLC who underwent baseline CT scans. The exclusion criteria included patients who received three or more lines of chemotherapy, those with insufficient clinical information, or those without treatment response evaluation.
RESULTS: A total of 136 patients were enrolled. Among the volumetric body composition parameters, patients in the highest quartiles (Q2-4) of the visceral fat index (VFI) exhibited a higher response rate to ICI therapy than those in the lowest quartile (Q1) of VFI (Q1 vs. Q2-4: 18.2% vs. 43.1%, p = 0.012). Patients with a VFI in Q2-4 had significantly prolonged progression-free survival (PFS) and overall survival (OS) (PFS, Q1 vs. Q2-4: 3.0 months vs. 6.4 months, p = 0.043; OS, Q1 vs. Q2-4: 5.6 months vs. 16.3 months, p = 0.004). Kaplan-Meier analysis based on the VFI and visceral fat Hounsfield unit (HU) revealed that patients with VFI in Q1 and HU in Q2-4 had the worst prognosis.
CONCLUSIONS: Visceral fat volume is significantly associated with treatment outcomes in ICI-treated patients with NSCLC. Moreover, fat quality may impact the treatment outcomes. This finding underscores the potential significance of both fat compartments and fat quality as prognostic indicators.
CRITICAL RELEVANCE STATEMENT: Visceral fat volume is significantly associated with treatment outcomes in ICI-treated patients with non-small cell lung cancer. Moreover, fat quality may impact the treatment outcomes. This finding underscores the potential significance of both fat compartments and fat quality as prognostic indicators.
KEY POINTS: • We found that visceral fat volume positively correlated with treatment response and survival in patients with non-small cell lung cancer receiving immune checkpoint inhibitors. • Additionally, a trend toward a negative correlation between visceral fat attenuation and survival was observed. • The findings highlight the prognostic utility of fat compartments and fat quality.

Keywords: Body composition; Computed tomography; Immune checkpoint inhibitor; Non-small cell lung cancer; Visceral fat

DOI: https://doi.org/10.1186/s13244-023-01532-4

Sci Rep. 2023 10 25. 13(1): 18302

SLC7A11, a potential immunotherapeutic target in lung adenocarcinoma.

Qingqing Shan, Chi Zhang, Yangke Li, Qunying Li, Yifan Zhang, Xue Li, Junqing Shi, Fengying Hu.

SLC7A11 has significant translational value in cancer treatment. However, there are few studies on whether SLC7A11 affects the immune status of lung adenocarcinoma (LUAD). Information on SLC7A11 expression and its impact on prognosis was obtained from the cancer genome atlas and gene expression omnibus databases. The differentially expressed genes (DEGs) were analysed by GO and KEGG. GSEA enrichment analysis was performed in the SLC7A11-high and SLC7A11-low groups. The relationship between SLC7A11 and tumour immunity, immune checkpoints, and immune cell infiltration was studied using R language. We analysed the correlation between SLC7A11 and chemotactic factors (CFs) and chemokine receptors using the TISIDB database. SLC7A11 is overexpressed in many tumours, including LUAD. The 5-year overall survival of patients in the SLC7A11-high group was lower than in the SLC7A11-low group. KEGG analysis found that the DEGs were enriched in ferroptosis signaling pathways. GSEA analysis found that the survival-related signaling pathways were enriched in the SLC7A11-low group. The SLC7A11-low group had higher immune scores and immune checkpoint expression. SLC7A11 was negatively correlated with many immune cells (CD8+ T cells, immature dendritic cells), CFs, chemokine receptors (such as CCL17/19/22/23, CXCL9/10/11/14, CCR4/6, CX3CR1, CXCR3) and MHCs (major histocompatibility complex). SLC7A11 may regulate tumour immunity and could be a potential therapeutic target for LUAD.

DOI: https://doi.org/10.1038/s41598-023-45284-z

Eur J Med Res. 2023 Oct 27. 28(1): 462

Synergistic anticancer activity of cisplatin combined with tannic acid enhances apoptosis in lung cancer through the PERK-ATF4 pathway.

Xiang Zheng, Lei Yang, Wei Zhai, Nana Geng, Zhimin Zhang, Xueying Li, Mingsong Wu.

BACKGROUND: Cisplatin (CDDP) is a common anticancer drug whose side effects limit its clinical applications. Tannins (TA) are plant-derived polyphenols that inhibit tumor growth in different types of cancer. Here, we evaluated the anticancer effect of TA combined with CDDP on lung cancer cell lines (GLC-82 and H1299) and investigated the underlying molecular mechanism of endoplasmic reticulum (ER) stress-induced apoptosis.METHODS: Cell lines were treated with CDDP, TA, and CDDP + TA, and the effect of the combination was assessed using MTT assay and observed under light and fluorescence microscopes. Cell apoptosis was detected by flow cytometry, and the levels of ERS apoptosis pathway related genes were valuated by qRT-PCR and western blotting. The effects of the drug combination on the tumors of nude mice injected with H1299 cells were investigated, and the expression of key factors in the ER stress apoptotic pathway was investigated.
RESULTS: The combination of CDDP and TA significantly inhibited lung cancer cell viability indicating a synergistic antitumoral effect. The mRNA and protein expression levels of key ER stress factors in the CDDP + TA group were considerably higher than those in the CDDP and TA groups, the tumor volume in tumor-bearing mice was the smallest, and the number of apoptotic cells and the protein expression levels of the key ER stress in the combination group were considerably higher.
CONCLUSIONS: The combination of TA and CDDP may produce synergistic antitumoral effects mediated by the PERK-ATF4-CHOP apoptotic axis, suggesting a novel adjuvant treatment for lung cancer.

Keywords: Cisplatin; Combination drugs; Endoplasmic reticulum stress; Lung cancer; Tannins

DOI: https://doi.org/10.1186/s40001-023-01420-z