bims-meluca 2024-03-03 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2024–03–03
nine papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge

KEAP1 promotes anti-tumor immunity by inhibiting PD-L1 expression in NSCLC.
Potential of Targeting TDO2 as the Lung Adenocarcinoma Treatment.
Cytokine and soluble programmed death-ligand 1 levels in serum and plasma of cancer patients treated with immunotherapy: Preanalytical and analytical considerations.
A signature of enhanced proliferation associated with response and survival to anti-PD-L1 therapy in early-stage non-small cell lung cancer.
Association of Nutritional Indices With Adverse Effects and Time-to-Treatment-Failure in Triple Therapy for Lung Cancer.
Identification of SLC2A1 as a predictive biomarker for survival and response to immunotherapy in lung squamous cell carcinoma.
Adeno-to-squamous transition drives resistance to KRAS inhibition in LKB1 mutant lung cancer.
Obesity and lung cancer - is programmed death ligand-1 (PD-1L) expression a connection?
Metabolism-focused CRISPR screen unveils mitochondrial pyruvate carrier 1 as a critical driver for PARP inhibitor resistance in lung cancer.

Cell Death Dis. 2024 Feb 27. 15(2): 175

KEAP1 promotes anti-tumor immunity by inhibiting PD-L1 expression in NSCLC.

Jinghan Li, Daiwang Shi, Siyi Li, Xiang Shi, Yu Liu, Yi Zhang, Gebang Wang, Chenlei Zhang, Tian Xia, Hai-Long Piao, Hong-Xu Liu.

Immunotherapy has become a prominent first-line cancer treatment strategy. In non-small cell lung cancer (NSCLC), the expression of PD-L1 induces an immuno-suppressive effect to protect cancer cells from immune elimination, which designates PD-L1 as an important target for immunotherapy. However, little is known about the regulation mechanism and the function of PD-L1 in lung cancer. In this study, we have discovered that KEAP1 serves as an E3 ligase to promote PD-L1 ubiquitination and degradation. We found that overexpression of KEAP1 suppressed tumor growth and promoted cytotoxic T-cell activation in vivo. These results indicate the important role of KEAP1 in anti-cancer immunity. Moreover, the combination of elevated KEAP1 expression with anti-PD-L1 immunotherapy resulted in a synergistic effect on both tumor growth and cytotoxic T-cell activation. Additionally, we found that the expressions of KEAP1 and PD-L1 were associated with NSCLC prognosis. In summary, our findings shed light on the mechanism of PD-L1 degradation and how NSCLC immune escape through KEAP1-PD-L1 signaling. Our results also suggest that KEAP1 agonist might be a potential clinical drug to boost anti-tumor immunity and improve immunotherapies in NSCLC.

DOI: https://doi.org/10.1038/s41419-024-06563-3
J Proteome Res. 2024 Feb 29.

Potential of Targeting TDO2 as the Lung Adenocarcinoma Treatment.

Er Jin, Zhidong Yin, Xiuxiu Zheng, Chenhong Yan, Kai Xu, Fouejio Yemele Eunice, Yue Gao.

  Tryptophan catabolism plays an important role in the metabolic reconnection in cancer cells to support special demands of tumor initiation and progression. The catabolic product of the tryptophan pathway, kynurenine, has the capability of suppressing the immune reactions of tumor cells. In this study, we conducted internal and external cohort studies to reveal the importance of tryptophan 2,3-dioxygenase (TDO) for lung adenocarcinoma (LUAD). Our study further demonstrated that the TDO2 expression was associated with the proliferation, survival, and invasion of LUAD cells, and targeting TDO2 for LUAD tumors could be a potential therapeutic strategy.

Keywords:  invasion; lung adenocarcinoma; metabolism; proliferation; tryptophan 2,3-dioxygenase

DOI:  https://doi.org/10.1021/acs.jproteome.3c00746
Int J Biol Markers. 2024 Mar;39(1): 9-22

Cytokine and soluble programmed death-ligand 1 levels in serum and plasma of cancer patients treated with immunotherapy: Preanalytical and analytical considerations.

Elia Cappelletto, Laura Tiozzo Fasiolo, Valentina Salizzato, Luisa Piccin, Alessio Fabozzi, Anna Contato, Paola Del Bianco, Giulia Pasello, Vanna Chiarion-Sileni, Massimo Gion, Aline S C Fabricio.

   AIM: To evaluate cytokine and soluble programmed death ligand-1 (sPD-L1) levels in the serum and plasma of cancer patients treated with immunotherapy, and to test different assays.
METHODS: Three Luminex xMAP assays and two ELLA microfluidic cartridges were used to screen 28 immune-related biomarkers in 38 paired serum and citrate-theophylline-adenosine-dipyridamole (CTAD) plasma samples collected from 10 advanced melanoma or non-small cell lung cancer (NSCLC) patients at different time points during immunotherapy.
RESULTS: Twenty-three of 28 biomarkers were detected both in serum and plasma by at least one of the assays, including IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p70, GM-CSF, IFN-γ, TNF-α, VEGF, IP-10, MCP-1, eotaxin, fractalkine, G-CSF, IFN-α, IL-1RA, IL-13, IL-17A, MIP-1β and sPD-L1. Conversely, FGF-2 and IL-1α were not detected in both matrices; GRO-α factor and EGF were detected only in serum and MIP-1α only in plasma. sPD-L1, MCP-1, IFN-γ, IL-8, MIP-1β and VEGF were, respectively, 1.15-, 1.44-, 1.83-, 2.43-, 2.82-, 6.72-fold higher in serum, whereas IL-10, IL-4, IL-2 and IL-5 were 1.05-, 1.19-, 1.92- and 2.17-fold higher, respectively, in plasma. IP-10 levels were higher in plasma but, as well as for VEGF, the bias serum versus plasma varied depending on the assay used (IP-10: -5.7% to -145%; VEGF: 115% to 165%). No significant differences were found for the remaining nine analyzed cytokines.
CONCLUSION: The cytokine and sPD-L1 levels may differ between serum and plasma samples collected from cancer patients treated with immunotherapy, and the results obtained can be influenced by the different characteristics of the tested assays. The standardization of pre-analytical and analytical procedures is therefore needed for the future implementation of these circulating biomarkers in clinical practice.

Keywords:  Cytokines; NSCLC; biomarker; cancer; immunotherapy; melanoma; plasma; pre-analytical‌; sPD-L1; serum

DOI:  https://doi.org/10.1177/03936155231226234
Cell Rep Med. 2024 Feb 13. pii: S2666-3791(24)00061-2. [Epub ahead of print] 101438

A signature of enhanced proliferation associated with response and survival to anti-PD-L1 therapy in early-stage non-small cell lung cancer.

Nasser K Altorki, Bhavneet Bhinder, Alain C Borczuk, Olivier Elemento, Vivek Mittal, Timothy E McGraw.

  In early-stage non-small cell lung cancer, the combination of neoadjuvant anti-PD-L1 and subablative stereotactic body radiation therapy (SBRT) is associated with higher rates of major pathologic response compared to anti-PD-L1 alone. Here, we identify a 140-gene set, enriched in genes characteristic of highly proliferating cells, associated with response to the dual therapy. Analysis of on-treatment transcriptome data indicate roles for T and B cells in response. The 140-gene set is associated with disease-free survival when applied to the combined trial arms. This 140-gene set identifies a subclass of tumors in all 7 of The Cancer Genome Atlas tumor types examined. Worse survival is associated with the 140-gene signature in 5 of these tumor types. Collectively, our data support that this 140-gene set, discovered in association with response to combined anti-PD-L1 and SBRT, identifies a clinically aggressive subclass of solid tumors that may be more likely to respond to immunotherapies.

Keywords:  NSCLC; biomarker immunotherapy response; combination immunotherapy radiation; immunotherapy; radiation therapy; rapidly proliferating tumors

DOI:  https://doi.org/10.1016/j.xcrm.2024.101438
In Vivo. 2024 Mar-Apr;38(2):38(2): 864-872

Association of Nutritional Indices With Adverse Effects and Time-to-Treatment-Failure in Triple Therapy for Lung Cancer.

Yasuhisa Hashino, Takumu Matushita, Tae Hatsuyama, Azusa Wakamoto, Keisuke Goto, Takanobu Hoshi, Kuninori Iwayama, Koichi Ohtaki, Takaki Toda, Hideki Sato.

   BACKGROUND/AIM: Recent lung cancer treatments include an immune checkpoint inhibitor (ICI) pembrolizumab, platinum-based agents, plus an additional cytotoxic anticancer agent. Nutritional indices, such as the geriatric nutritional risk index (GNRI) and the prognostic nutritional index (PNI), are known to correlate with the prognosis of cancer chemotherapy. Several previous studies have investigated the relationship between PNI and treatment response in non-small cell lung cancer patients, reporting significantly increased OS and PFS in the high PNI group before treatment. However, the relationship between the three-drug combination and GNRI/PNI is unclear. The current study aimed to investigate the association of nutritional indices with duration of treatment success and occurrence of side effects in triple therapy.
PATIENTS AND METHODS: Seventy-two patients with non-small cell lung cancer, treated with combination of carboplatin, pemetrexed, and pembrolizumab from November 2019 to September 30, 2022, were classified into two groups (High and Low) for GNRI and PNI, and a retrospective study was performed.
RESULTS: In terms of time-to-treatment-failure (TTF), univariate and multivariate Cox proportional hazards regression analysis showed the Low-PNI group to have significantly shorter TTF than the High-PNI group (p=0.006); multivariate analysis results also showed PNI as a factor affecting TTF (HR=2.791, 95%CI=1.362-5.721, p=0.005). On the other hand, GNRI was not shown to be a factor affecting TTF.
CONCLUSION: PNI at the start of treatment was an independent prognostic factor affecting treatment success time (TTF) in non-small cell lung cancer patients receiving triple therapy. However, PNI was not shown to be a prognostic predictor of irAE development.

Keywords:  Pembrolizumab; geriatric nutritional risk index; immunotherapy; non-small cell lung cancer; prognostic factor; prognostic nutritional index

DOI:  https://doi.org/10.21873/invivo.13512
Comput Biol Med. 2024 Feb 22. pii: S0010-4825(24)00267-1. [Epub ahead of print]171 108183

Identification of SLC2A1 as a predictive biomarker for survival and response to immunotherapy in lung squamous cell carcinoma.

Bo Hao, Huixing Dong, Rui Xiong, Congkuan Song, Chenzhen Xu, Ning Li, Qing Geng.

   BACKGROUND: As one of the common subtypes of non-small lung cancer, lung squamous cell carcinoma (LUSC) patients with advanced stage have few choices of treatment strategies. Therefore, it is urgent to discover genes that are associated with the survival and efficacy of immunotherapies.
METHOD: Differential gene expression analyses were conducted using TCGA LUSC bulk-sequencing and single-cell RNA-sequencing data. Prognostic genes were identified from the TCGA LUSC cohort. Protein expression validation and survival analyses were performed. Experiments were conducted to explore the underlying mechanisms. In addition, the correlation between gene expression and pathological response to adjuvant immunochemotherapy was also investigated.
RESULTS: After a series of bioinformatic analyses, solute carrier family 2 member 1(SLC2A1), encoding glucose transporter-1 (GLUT1), was found to be differentially expressed between tumor and normal tissues. GLUT1 was subsequently identified as an independent prognostic factor for LUSC. GSEA analysis revealed the glycolysis metabolism pathway of KEGG enriched in SLC2A1high tumor tissues. LASSO analyses revealed that tumor tissues with high expression of SLC2A1 were associated with high levels of protein lactylation. We found that SLC2A1 was preferentially expressed by SPP1+ macrophages in the tumor microenvironment, and the expression of SLC2A1 was associated with the abundance of SPP1+ macrophages. Immunofluorescence demonstrated GLUT1 and HIF1α colocalization in tumor-infiltrating macrophages. In vitro experiments showed HIF-1α-induced macrophage polarization under hypoxia, and GLUT1 inhibition blocked this polarization. In addition, SLC2A1 was negatively associated with the common immune checkpoint molecules, such as programmed cell death 1(PD-1), T cell immunoreceptor with Ig and ITIM domains (TIGIT), cytotoxic T-lymphocyte associated protein 4 (CTLA4) and lymphocyte activating 3 (LAG3), while showed a positive association with CD44. Finally, we observed that there was a significant correlation between pre-adjuvant-treatment GLUT1 expression and the pathological response.
CONCLUSION: SLC2A1 expression was differentially upregulated in tumor tissues, and elevated GLUT1 expression was associated with worse survival and poor pathological response to adjuvant immunochemotherapy. Upregulation of GLUT1 promoted macrophage polarization into the M2 phenotype. The findings will contribute to guiding the treatment selection for LUSC patients and providing personalized immunotherapy strategies.

Keywords:  GLUT1; Glycolysis; Immunotherapy; Lung squamous cell carcinoma; SLC2A1

DOI:  https://doi.org/10.1016/j.compbiomed.2024.108183
Cancer Cell. 2024 Feb 20. pii: S1535-6108(24)00036-9. [Epub ahead of print]

Adeno-to-squamous transition drives resistance to KRAS inhibition in LKB1 mutant lung cancer.

Xinyuan Tong, Ayushi S Patel, Eejung Kim, Hongjun Li, Yueqing Chen, Shuai Li, Shengwu Liu, Julien Dilly, Kevin S Kapner, Ningxia Zhang, Yun Xue, Laura Hover, Suman Mukhopadhyay, Fiona Sherman, Khrystyna Myndzar, Priyanka Sahu, Yijun Gao, Fei Li, Fuming Li, Zhaoyuan Fang, Yujuan Jin, Juntao Gao, Minglei Shi, Satrajit Sinha, Luonan Chen, Yang Chen, Thian Kheoh, Wenjing Yang, Itai Yanai, Andre L Moreira, Vamsidhar Velcheti, Benjamin G Neel, Liang Hu, James G Christensen, Peter Olson, Dong Gao, Michael Q Zhang, Andrew J Aguirre, Kwok-Kin Wong, Hongbin Ji.

  KRASG12C inhibitors (adagrasib and sotorasib) have shown clinical promise in targeting KRASG12C-mutated lung cancers; however, most patients eventually develop resistance. In lung patients with adenocarcinoma with KRASG12C and STK11/LKB1 co-mutations, we find an enrichment of the squamous cell carcinoma gene signature in pre-treatment biopsies correlates with a poor response to adagrasib. Studies of Lkb1-deficient KRASG12C and KrasG12D lung cancer mouse models and organoids treated with KRAS inhibitors reveal tumors invoke a lineage plasticity program, adeno-to-squamous transition (AST), that enables resistance to KRAS inhibition. Transcriptomic and epigenomic analyses reveal ΔNp63 drives AST and modulates response to KRAS inhibition. We identify an intermediate high-plastic cell state marked by expression of an AST plasticity signature and Krt6a. Notably, expression of the AST plasticity signature and KRT6A at baseline correlates with poor adagrasib responses. These data indicate the role of AST in KRAS inhibitor resistance and provide predictive biomarkers for KRAS-targeted therapies in lung cancer.

Keywords:  KRAS inhibitor; KRT6A; LKB1; adeno-to-squamous transition, AST; organoid

DOI:  https://doi.org/10.1016/j.ccell.2024.01.012
Arch Med Sci. 2024 ;20(1): 313-316

Obesity and lung cancer - is programmed death ligand-1 (PD-1L) expression a connection?

Jakub Krzysztof Gałązka, Marcin Czeczelewski, Tomasz Kucharczyk, Katarzyna Szklener, Sławomir Mańdziuk.

   Introduction: In this retrospective study, the authors evaluated whether obesity-induced immunomodulation impacts the expression of programmed death ligand-1 (PD-1L) in lung cancer cells.Methods: A retrospective cross-sectional study was performed. The study included 67 patients. The data did not have a normal distribution.
Results: For women, using ANOVA test (p = 0.050) with post-hoc analysis, a statistically significant difference in expression was found between women with overweight and women with normal weight (p = 0.040).
Conclusions: Apart from the above, the authors did not find any statistically significant correlation between PD-1L expression on lung cancer cells and body mass index, either in the whole group or in histological subgroups.

Keywords:  lung cancer; obesitology; obesity; oncology; programmed death ligand-1; pulmonology

DOI:  https://doi.org/10.5114/aoms/175470
Mol Carcinog. 2024 Feb 27.

Metabolism-focused CRISPR screen unveils mitochondrial pyruvate carrier 1 as a critical driver for PARP inhibitor resistance in lung cancer.

Takashi Furusawa, Renzo Cavero, Yue Liu, Haojian Li, Xia Xu, Thorkell Andresson, William Reinhold, Olivia White, Myriem Boufraqech, Thomas J Meyer, Oliver Hartmann, Markus E Diefenbacher, Yves Pommier, Urbain Weyemi.

  Homologous recombination (HR) and poly ADP-ribosylation are partially redundant pathways for the repair of DNA damage in normal and cancer cells. In cell lines that are deficient in HR, inhibition of poly (ADP-ribose) polymerase (poly (ADP-ribose) polymerase [PARP]1/2) is a proven target with several PARP inhibitors (PARPis) currently in clinical use. Resistance to PARPi often develops, usually involving genetic alterations in DNA repair signaling cascades, but also metabolic rewiring particularly in HR-proficient cells. We surmised that alterations in metabolic pathways by cancer drugs such as Olaparib might be involved in the development of resistance to drug therapy. To test this hypothesis, we conducted a metabolism-focused clustered regularly interspaced short palindromic repeats knockout screen to identify genes that undergo alterations during the treatment of tumor cells with PARPis. Of about 3000 genes in the screen, our data revealed that mitochondrial pyruvate carrier 1 (MPC1) is an essential factor in desensitizing nonsmall cell lung cancer (NSCLC) lung cancer lines to PARP inhibition. In contrast to NSCLC lung cancer cells, triple-negative breast cancer cells do not exhibit such desensitization following MPC1 loss and reprogram the tricarboxylic acid cycle and oxidative phosphorylation pathways to overcome PARPi treatment. Our findings unveil a previously unknown synergistic response between MPC1 loss and PARP inhibition in lung cancer cells.

Keywords:  CRISPR screen; DNA damage response; NSCLC; PARP inhibitor; breast cancer; metabolism

DOI:  https://doi.org/10.1002/mc.23705