bims-meluca 2023-04-23 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2023–04–23
seven papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge

Distinct Nrf2 Signaling Thresholds Mediate Lung Tumor Initiation and Progression.
Distinct circulating cytokine/chemokine profiles correlate with clinical benefit of immune checkpoint inhibitor monotherapy and combination therapy in advanced non-small cell lung cancer.
Combined systemic immune-inflammatory index and prognostic nutritional index predict outcomes in advanced non-small cell lung cancer patients receiving platinum-doublet chemotherapy.
Multi-target angiogenesis inhibitor combined with PD-1 inhibitors may benefit advanced non-small cell lung cancer patients in late line after failure of EGFR-TKI therapy.
Overall survival in patients with advanced non-small cell lung cancer with KRAS G12C mutation with or without STK11 and/or KEAP1 mutations in a real-world setting.
Tumor-infiltrating CD36+CD8+T cells determine exhausted tumor microenvironment and correlate with inferior response to chemotherapy in non-small cell lung cancer.
Loss of BLK expression as a potential predictor of poor prognosis and immune checkpoint blockade response in NSCLC and contribute to tumor progression.

Cancer Res. 2023 Apr 16. pii: CAN-22-3848. [Epub ahead of print]

Distinct Nrf2 Signaling Thresholds Mediate Lung Tumor Initiation and Progression.

Janine M DeBlasi, Aimee Falzone, Samantha Caldwell, Nicolas Prieto-Farigua, Justin R Prigge, Edward E Schmidt, Iok In Christine Chio, Florian A Karreth, Gina M DeNicola.

Mutations in the KEAP1-NRF2 pathway occur in up to a third of non-small cell lung cancer (NSCLC) cases and often confer resistance to therapy and poor outcomes. Here, we developed murine alleles of the KEAP1 and NRF2 mutations found in human NSCLC and comprehensively interrogated their impact on tumor initiation and progression. Chronic NRF2 stabilization by Keap1 or Nrf2 mutation was not sufficient to induce tumorigenesis, even in the absence of tumor suppressors p53 or LKB1. When combined with KrasG12D/+, constitutive NRF2 activation promoted lung tumor initiation and early progression of hyperplasia to low-grade tumors but impaired their progression to advanced-grade tumors, which was reversed by NRF2 deletion. Finally, NRF2 overexpression in KEAP1 mutant human NSCLC cell lines was detrimental to cell proliferation, viability, and anchorage-independent colony formation. Collectively, these results establish the context-dependence and activity threshold for NRF2 during the lung tumorigenic process.

DOI: https://doi.org/10.1158/0008-5472.CAN-22-3848
Cancer Med. 2023 Apr 16.

Distinct circulating cytokine/chemokine profiles correlate with clinical benefit of immune checkpoint inhibitor monotherapy and combination therapy in advanced non-small cell lung cancer.

Yue Hu, Shixun Li, He Xiao, Yanli Xiong, Xianfeng Lu, Xiao Yang, Wei Luo, Jiamin Luo, Shiheng Zhang, Yi Cheng, Lei Zhang, Xiaoyan Dai, Yuxin Yang, Dong Wang, Mengxia Li.

   BACKGROUND: An ever-increasing number of efforts are focused on identifying effective biomarkers for immune checkpoint inhibitors (ICIs). Cytokines and chemokines are critical to tumor growth, metastasis, tumor angiogenesis, and the immune response against tumor cells. In the study here, we determined the correlation between circulating cytokines/chemokines and the clinical benefit of ICIs for non-small cell lung cancer (NSCLC) patients.
METHODS: Peripheral blood samples were collected before and during treatment (at 12th week). Plasma levels of cytokines/chemokines and specific stress response markers were measured using the Bio-Plex Pro Human Cytokines Grp I Panel (27-plex), an APEX1 detection kit, and a human LAP(TGF-β1) immunoassay kit. A Mann-Whitney U-test or Wilcoxon signed-rank test and a Cox proportional hazards model were employed for statistical analysis.
RESULTS: In the ICI monotherapy cohort, a high level of IL-6 at pretreatment or an elevation of IL-6, IL-8, FGF2, CXCL10, CCR1, PDFGB, TNF, and APEX1 posttreatment was associated with poor progress-free survival (PFS). A posttreatment elevation (defined herein as change rate) of CXCL10 was also associated with poor overall survival (OS). In the combinational therapy group, a high level of IL-12, IL-17A, FGF2, VEGF, and APEX1 at pretreatment and an elevation of CCL2 posttreatment were associated with poor PFS. A high level of IL-9, FGF2, PDFGB, CCL4, TFGB, and APEX1 at pretreatment and an elevation of IL-13, CSF2, and CCL2 at posttreatment were associated with poor OS of patients receiving combination therapy.
CONCLUSIONS: The study here suggests that circulating cytokines/chemokines are feasible, noninvasive biomarkers for predicting clinical benefit of ICI treatment for NSCLC. Distinct circulating factor profiles were observed in individuals receiving ICI monotherapy or combination therapy.

Keywords:  PD-1/PD-L1; biomarkers; chemokines; cytokines; non-small cell lung cancer

DOI:  https://doi.org/10.1002/cam4.5918
Front Oncol. 2023 ;13 996312

Combined systemic immune-inflammatory index and prognostic nutritional index predict outcomes in advanced non-small cell lung cancer patients receiving platinum-doublet chemotherapy.

Ruiyun Fan, Ying Chen, Guopeng Xu, Wen Pan, Yantian Lv, Zhongwei Zhang.

   Background: Systemic immune-inflammatory index (SII) and prognostic nutritional index (PNI) could evaluate the therapeutic efficacy and prognosis in different tumors. However, no studies investigated the SII-PNI score to predict outcomes in non-small cell lung cancer (NSCLC) patients treated with platinum-doublet chemotherapy. The aim of this study was to investigate the SII-PNI score in predicting outcomes in non-small cell lung cancer (NSCLC) patients treated with platinum-doublet chemotherapy.
Materials and methods: Our study retrospectively analyzed clinical data from 124 patients with advanced NSCLC receiving platinum-doublet chemotherapy. The SII and PNI were calculated based on peripheral blood cell counts and serum albumin, and the optimal cut-off values were determined using receiver operating characteristic (ROC). All patients were divided into three groups according to the SII-PNI score. The association between the SII-PNI score and the clinicopathological characteristics of the patients was examined. The Kaplan-Meier and Cox regression models were used to assess progression-free survival (PFS)and overall survival (OS).
Results: There was no significant correlation between SII, PNI at baseline and chemotherapy response in patients with advanced NSCLC (p>0.05). However, after receiving 4 cycles of platinum-doublet chemotherapy, the SII of the SD group (p=0.0369) and PD group (p=0.0286) was significantly higher than that of the PR group. At the same time, the PNI of the SD group (p=0.0112) and the PD group (p=0.0007) was significantly lower than that of the PR group. The PFS of patients with SII-PNI scores of 0, 1, and 2 were 12.0, 7.0, and 5.0 months, and the OS of patients with SII-PNI scores of 0, 1, and 2 were 34.0, 17.0, and 10.5 months, respectively. There was statistical significance among the three groups (all p <0.001). Multivariate analyses showed that the chemotherapy response of progressive disease (PD) (HR, 3.508; 95% CI, 1.546-7.960; p=0.003) and SII-PNI score of 2 (HR, 4.732; 95% CI, 2.561-8.743; p < 0.001) were independently associated with a shorter OS. The uses of targeted drugs (HR, 0.543; 95% CI, 0.329-0.898; p=0.017) and immune checkpoint inhibitors (HR, 0.218; 95% CI, 0.081-0.584; p=0.002) were protective factors for OS in patients with NSCLC.
Conclusion: Compared with baseline parameters, the correlation between SII, PNI after 4 cycles of chemotherapy and the chemotherapy effect was more significant. The SII-PNI score after 4 cycles of chemotherapy is an effective prognostic biomarker for advanced NSCLC patients treated with platinum-doublet chemotherapy. Patients with a higher SII-PNI score had a worse prognosis.

Keywords:  first-line chemotherapy; non-small cell lung cancer; prognostic nutritional index; survival; systemic immune-inflammation index

DOI:  https://doi.org/10.3389/fonc.2023.996312
Int J Cancer. 2023 Apr 20.

Multi-target angiogenesis inhibitor combined with PD-1 inhibitors may benefit advanced non-small cell lung cancer patients in late line after failure of EGFR-TKI therapy.

Lian Yu, Yaohua Hu, Jianlin Xu, Rong Qiao, Hua Zhong, Baohui Han, Jinjing Xia, Runbo Zhong.

  Treatments for NSCLC patients with EGFR-TKI resistance are limited. Given that immunotherapy and antiangiogenic agents may have synergistic antitumor effects, we aimed to analyze the effect of multi-target angiogenesis inhibitor anlotinib and immune checkpoint inhibitors (ICIs) combination therapy in NSCLC patients who failed EGFR-TKI. The medical records of lung adenocarcinoma (LUAD) patients with EGFR-TKI resistance were reviewed. After EGFR-TKI resistance, patients who simultaneously received anlotinib and ICIs were enrolled in the observation group, and those who received platinum-pemetrexed chemotherapy were included in the control group. A total of 80 LUAD patients were reviewed and allocated to the anlotinib and ICIs combination therapy (n = 38) and chemotherapy (n = 42) groups. A re-biopsy was performed in all patients in the observation group before the administration of anlotinib and ICIs. The median follow-up was 15.63 months (95% CI: 12.19-19.08). Combination therapy exhibited better PFS (median PFS: 4.33 months [95% CI: 2.62-6.05] vs 3.60 months [95% CI: 2.48-4.73], P = .005), and better OS (median OS: 14.17 months [95% CI: 10.17-18.17] vs 9.00 months [95% CI: 6.92-11.08], P = .029) than chemotherapy. Most patients (73.7%) received combination therapy as fourth and later lines of therapy, with a median PFS of 4.03 months (95% CI: 2.05-6.02) and a median OS of 13.80 months (95% CI: 8.25-19.36). The disease control rate was 92.1%. Four patients discontinued the combination therapy due to adverse events, but the other adverse reactions were manageable and reversible. The combination of anlotinib and PD-1 inhibitors is a promising regimen for the late-line treatment of LUAD patients with EGFR-TKI resistance.

Keywords:  EGFR; PD-1; antiangiogenics; non-small cell lung cancer

DOI:  https://doi.org/10.1002/ijc.34536
BMC Cancer. 2023 Apr 17. 23(1): 352

Overall survival in patients with advanced non-small cell lung cancer with KRAS G12C mutation with or without STK11 and/or KEAP1 mutations in a real-world setting.

Cristina Julian, Navdeep Pal, Anda Gershon, Marie Evangelista, Hans Purkey, Peter Lambert, Zhen Shi, Qing Zhang.

   BACKGROUND: KRAS mutations occur frequently in advanced non-small cell lung cancer (aNSCLC); the G12C mutation is the most prevalent. Alterations in STK11 or KEAP1 commonly co-occur with KRAS mutations in aNSCLC. Using real-world data, we assessed the effect of KRAS G12C mutation with or without STK11 and/or KEAP1 mutations on overall survival (OS) in patients with aNSCLC receiving cancer immunotherapy (CIT), chemotherapy, or both in first line (1L) and second line (2L).
METHODS: Patients diagnosed with aNSCLC between January 2011 and March 2020 in a clinico-genomic database were included. Cox proportional hazards models adjusted for left truncation, baseline demographics and clinical characteristics were used to analyze the effect of STK11 and/or KEAP1 co-mutational status on OS in patients with KRAS wild-type (WT) or G12C mutation.
RESULTS: Of 2715 patients with aNSCLC without other actionable driver mutations, 1344 (49.5%) had KRAS WT cancer, and 454 (16.7%) had KRAS G12C-positive cancer. At 1L treatment start, significantly more patients with KRAS G12C-positive cancer were female, smokers, and had non-squamous histology, a higher prevalence of metastasis and programmed death-ligand 1 positivity than those with KRAS WT cancer. Median OS was comparable between patients with KRAS G12C-positive and KRAS WT cancer when receiving chemotherapy or combination CIT and chemotherapy in the 1L or 2L. Median OS was numerically longer in patients with KRAS G12C vs KRAS WT cancer treated with 1L CIT (30.2 vs 10.6 months, respectively) or 2L CIT (11.3 vs 7.6 months, respectively). Co-mutation of STK11 and KEAP1 was associated with significantly shorter OS in patients receiving any type of 1L therapy, regardless of KRAS G12C mutational status.
CONCLUSIONS: This real-world study showed that patients with KRAS G12C-positive or KRAS WT cancer have similar OS in the 1L or 2L when treated with chemotherapy or combination CIT and chemotherapy. In contrast to aNSCLC patients with EGFR or ALK driver mutations, patients with KRAS G12C-positive cancer may benefit from CIT monotherapy. Co-mutation of STK11 and KEAP1 was associated with significantly shorter survival, independent of KRAS G12C mutational status, reflecting the poor prognosis and high unmet need in this patient population.

Keywords:  Chemotherapy; Immunotherapy; KEAP1; KRAS G12C; Metastasis; Non-small cell lung cancer; STK11

DOI:  https://doi.org/10.1186/s12885-023-10778-6
BMC Cancer. 2023 Apr 21. 23(1): 367

Tumor-infiltrating CD36+CD8+T cells determine exhausted tumor microenvironment and correlate with inferior response to chemotherapy in non-small cell lung cancer.

Yong-Qiang Ao, Jian Gao, Ling-Xian Zhang, Jie Deng, Shuai Wang, Miao Lin, Hai-Kun Wang, Jian-Yong Ding, Jia-Hao Jiang.

   BACKGROUND: The scavenger receptor CD36 was reported to be highly expressed on tumor-infiltrating CD8+ T cells, but the clinical role remains obscure. This study aims to explore the infiltration and clinical value of CD36+CD8+ T cells in NSCLC.
METHODS: Immunohistochemistry and immunofluorescence were conducted for survival analyses and immunological evaluation in 232 NSCLC patients in Zhongshan Hospital. Flow cytometry analyses were carried out to assess the immune cells from fresh tumor samples, non-tumor tissues and peripheral blood. In vitro tumor infiltrating lymphocytes cultures were conducted to test the effect of CD36 blockage.
RESULTS: Accumulation of CD36+CD8+ T cells in tumor tissues was correlated with more advanced stage (p < 0.001), larger tumor size (p < 0.01), and lymph node metastasis (p < 0.0001) in NSCLC. Moreover, high infiltration of CD36+CD8+ T cells indicated poor prognosis in terms of both overall survival (OS) and recurrence-free survival (RFS) and inferior chemotherapy response. CD36+CD8+ T cells showed decreased GZMB (p < 0.0001) and IFN-γ (p < 0.001) with elevated PD-1 (p < 0.0001) and TIGIT (p < 0.0001). Analysis of tumor-infiltrating immune cell landscape revealed a positive correlation between CD36+CD8+ T cells and Tregs (p < 0.01) and M2-polarized macrophages (p < 0.01) but a negative correlation with Th1 (p < 0.05). Notably, inhibition of CD36 partially restored the cytotoxic function of CD8+ T cells by producing more GZMB and IFN-γ.
CONCLUSION: CD36+CD8+ T cells exhibit impaired immune function and high infiltration of CD36+CD8+ T cells indicated poor prognosis and inferior chemotherapy response in NSCLC patients. CD36 could be a therapeutic target in combination with chemotherapy in NSCLC patients.

Keywords:  CD36+CD8+ T cells; Chemotherapy; NSCLC; Prognosis; Tumor microenvironment

DOI:  https://doi.org/10.1186/s12885-023-10836-z
Transl Oncol. 2023 Apr 15. pii: S1936-5233(23)00057-8. [Epub ahead of print]33 101671

Loss of BLK expression as a potential predictor of poor prognosis and immune checkpoint blockade response in NSCLC and contribute to tumor progression.

Yingqi Xu, Jianlin Xu, Rong Qiao, Hua Zhong, Jinjing Xia, Runbo Zhong.

   BACKGROUND: Immune checkpoint blockade (ICB) has been proved to have significant anti-tumor effect in the clinical treatment of non-small cell lung cancer (NSCLC). Therefore, biomarkers predicting ICB response can provide better treatment for patients with NSCLC.
METHODS: Differential expression genes (DEGs) were identified by ImmuCellAI database. Copy number alteration (CNA) was analyzed by cBioPortal. The predicted efficiency of 4 genes on cancer immunotherapy was assessed by ROC analysis. The survival value of BLK was analyzed by Kaplan-Meier plotter and Prognoscan analysis. Clinical significance of BLK IHC-TMA score in NSCLC was also explored. The CCK-8 assay, wound healing assay, western blot assay in vitro and subcutaneous xenograft experiments in vivo were used for investigating the functions of BLK. The RNA-sequencing were performed to screen BLK regulated genes and conducted for GO/KEGG enrichment analysis. The transcriptional regulatory factor of BLK promoter region was predicted by ChIP-seq analysis.
RESULTS: 39 common DEGs between ICB Response (R) group and No Response (NR) group with NSCLC were identified, in which the CNA frequency of BLK deletion (> 6%) was found. The predicted efficiency of BLK on immunotherapy was performed best in NSCLC (AUC>0.7). Low expression of BLK was related to NSCLC with significantly poor prognosis. BLK overexpression can inhibit growth of NSCLC via activating apoptosis pathway, inhibiting the G2M checkpoint and Glycolysis pathway. The enrichment analysis indicated that BLK regulated genes related to oncogenic potential in NSCLC. Besides, BLK expression was inhibited via H3K27me3 modification in A549 and H1299 cells. BLK mRNA level was negatively correlated with methylation and positively correlated with the tumor purity in NSCLC.
CONCLUSION: Our study provides strong evidence that low expression of BLK may serve as a biomarker for poor prognosis in NSCLC, while response to ICB therapy and contributes to NSCLC tumor progression.

Keywords:  BLK; H3K27me3; Immune checkpoint blockade (ICB); Non-small cell lung cancer (NSCLC); RNA sequencing; Tumor growth; prognosis

DOI:  https://doi.org/10.1016/j.tranon.2023.101671