bims-meluca 2025-01-05 papers

Cancer Immunol Immunother. 2025 Jan 03. 74(2): 58

Role of the HGF/c-MET pathway in resistance to immune checkpoint inhibitors in advanced non-small cell lung cancer.

Assya Akli, Paul Takam Kamga, Catherine Julie, Claude Capron, Adrien Costantini, Coraline Dumenil, Jennifer Dumoulin, Violaine Giraud, Florence Parent, Andrei Seferian, Catherine Guettier, Mathieu Glorion, Elisabeth Longchampt, Jean-François Emile, Étienne Giroux-Leprieur.

Most of advanced non-small cell lung cancer (NSCLC) patients will experience tumor progression with immunotherapy (IO). Preliminary data suggested an association between high plasma HGF levels and poor response to IO in advanced NSCLC. Our study aimed to evaluate further the role of the HGF/MET pathway in resistance to IO in advanced NSCLC. We included retrospectively 82 consecutive NSCLC patients from two academic hospitals. Among them, 49 patients received ICIs alone or in combination with chemotherapy (CT), while 33 patients received chemotherapy alone as the control group. We analyzed plasma HGF levels by ELISA and expression of PD-L1, MET/phospho-MET, and CD8+ T-Cell infiltration on lung tumor tissue by immunohistochemistry. We investigated the contribution of HGF/MET to IO response by culturing peripheral blood mononuclear cells (PBMC) with or without pembrolizumab, with recombinant HGF, or cocultured with NSCLC patients-derived explants. Additionally, c-MET inhibitors were used to evaluate the contribution of MET activation in NSCLC-mediated immunosuppression. High HGF levels were associated with high progression rate with IO (p = 0.0092), but not with CT. ELISA analysis of supernatants collected from cultured NSCLC cells showed that HGF was produced by tumor cells. Furthermore, when activated PBMCs were cultured in the presence of recombinant HGF or on NSCLC monolayer, the proliferation of CD3+CD8+ lymphocytes was inhibited, even in the presence of pembrolizumab. The addition of HGF/MET inhibitors restored lymphocyte activation and induced IFNγ production. In conclusion, inhibiting the HGF/MET signaling pathway could be a promising approach to enhance the efficacy of immunotherapy.

Keywords: HGF; MET; immunotherapy; non-small cell lung cancer; resistance

DOI: https://doi.org/10.1007/s00262-024-03882-4

Front Pharmacol. 2024 ;15 1516650

Metabolic reprogramming in lung cancer and its clinical implication.

Qingqiu Huang, Lisha Fan, Mingjing Gong, Juntong Ren, Chen Chen, Shenglong Xie.

Lung cancer has posed a significant challenge to global health, and related study has been a hot topic in oncology. This article focuses on metabolic reprogramming of lung cancer cells, a process to adapt to energy demands and biosynthetic needs, supporting the proliferation and development of tumor cells. In this study, the latest studies on lung cancer tumor metabolism were reviewed, including the impact of metabolic products and metabolic enzymes on the occurrence and development of lung cancer, as well as the progress in the field of lung cancer treatment targeting relevant metabolic pathways. This provides some promising potential directions into exploring lung cancer tumor metabolism and helps researchers to better understand lung cancer.

Keywords: amino acid metabolism; glucose; lipid metabolism; lung cancer; metabolic reprogramming

DOI: https://doi.org/10.3389/fphar.2024.1516650

BMC Cancer. 2024 Dec 30. 24(1): 1590

Early changes of peripheral circulating immune subsets induced by PD-1 inhibitors in patients with advanced malignant melanoma and non-small cell lung cancer.

Simona Borilova, Peter Grell, Iveta Selingerova, Lenka Gescheidtova, Marie Mlnarikova, Ondrej Bilek, Radek Lakomy, Alexandr Poprach, Jan Podhorec, Igor Kiss, Rostislav Vyzula, Barbora Vavrusakova, Jiri Nevrlka, Lenka Zdrazilova-Dubska.

BACKGROUND: Immune checkpoint inhibitors (ICIs), including those targeting PD-1, are currently used in a wide range of tumors, but only 20-40% of patients achieve clinical benefit. The objective of our study was to find predictive peripheral blood-based biomarkers for ICI treatment.
METHODS: In 41 patients with advanced malignant melanoma (MM) and NSCLC treated with PD-1 inhibitors, we analyzed peripheral blood-based immune subsets by flow cytometry before treatment initialization and the second therapy dose. Specifically, we assessed basic blood differential count, overall T cells and their subgroups, B cells, and myeloid-derived suppressor cells (MDSC). In detail, CD4 + and CD8 + T cells were assessed according to their subtypes, such as central memory T cells (TCM), effector memory T cells (TEM), and naïve T cells (TN). Furthermore, we also evaluated the predictive value of CD28 and ICOS/CD278 co-expression on T cells.
RESULTS: Patients who achieved disease control on ICIs had a significantly lower baseline proportion of CD4 + TEM (p = 0.013) and tended to have a higher baseline proportion of CD4 + TCM (p = 0.059). ICI therapy-induced increase in Treg count (p = 0.012) and the proportion of CD4 + TN (p = 0.008) and CD28 + ICOS- T cells (p = 0.012) was associated with disease control. Patients with a high baseline proportion of CD4 + TCM and a low baseline proportion of CD4 + TEM showed significantly longer PFS (p = 0.011, HR 2.6 and p ˂ 0.001, HR 0.23, respectively) and longer OS (p = 0.002, HR 3.75 and p ˂ 0.001, HR 0.15, respectively). Before the second dose, the high proportion of CD28 + ICOS- T cells after ICI therapy initiation was significantly associated with prolonged PFS (p = 0.017, HR 2.51) and OS (p = 0.030, HR 2.69). Also, a high Treg count after 2 weeks of ICI treatment was associated with significantly prolonged PFS (p = 0.016, HR 2.33).
CONCLUSION: In summary, our findings suggest that CD4 + TEM and TCM baselines and an early increase in the Treg count induced by PD-1 inhibitors and the proportion of CD28 + ICOS- T cells may be useful in predicting the response in NSCLC and MM patients.

Keywords: Antitumor immunity; Immune checkpoint inhibitors; Peripheral blood circulating immune subsets; Predictive biomarker

DOI: https://doi.org/10.1186/s12885-024-13351-x

Front Immunol. 2024 ;15 1361992

Multi-omics analysis-based clinical and functional significance of a novel prognostic and immunotherapeutic gene signature derived from amino acid metabolism pathways in lung adenocarcinoma.

Huihui Xiang, Rika Kasajima, Koichi Azuma, Tomoyuki Tagami, Asami Hagiwara, Yoshiro Nakahara, Haruhiro Saito, Yuka Igarashi, Feifei Wei, Tatsuma Ban, Mitsuyo Yoshihara, Yoshiyasu Nakamura, Shinya Sato, Shiro Koizume, Tomohiko Tamura, Tetsuro Sasada, Yohei Miyagi.

Background: Studies have shown that tumor cell amino acid metabolism is closely associated with lung adenocarcinoma (LUAD) development and progression. However, the comprehensive multi-omics features and clinical impact of the expression of genes associated with amino acid metabolism in the LUAD tumor microenvironment (TME) are yet to be fully understood.
Methods: LUAD patients from The Cancer Genome Atlas (TCGA) database were enrolled in the training cohort. Using least absolute shrinkage and selection operator Cox regression analysis, we developed PTAAMG-Sig, a signature based on the expression of tumor-specific amino acid metabolism genes associated with overall survival (OS) prognosis. We evaluated its predictive performance for OS and thoroughly explored the effects of the PTAAMG-Sig risk score on the TME. The risk score was validated in two Gene Expression Omnibus (GEO) cohorts and further investigated against an original cohort of chemotherapy combined with immune checkpoint inhibitors (ICIs). Somatic mutation, chemotherapy response, immunotherapy response, gene set variation, gene set enrichment, immune infiltration, and plasma-free amino acids (PFAAs) profile analyses were performed to identify the underlying multi-omics features.
Results: TCGA datasets based PTAAMG-Sig model consisting of nine genes, KYNU, PSPH, PPAT, MIF, GCLC, ACAD8, TYRP1, ALDH2, and HDC, could effectively stratify the OS in LUAD patients. The two other GEO-independent datasets validated the robust predictive power of PTAAMG-Sig. Our differential analysis of somatic mutations in the high- and low-risk groups in TCGA cohort showed that the TP53 mutation rate was significantly higher in the high-risk group and negatively correlated with OS. Prediction from transcriptome data raised the possibility that PTAAMG-Sig could predict the response to chemotherapy and ICIs therapy. Our immunotherapy cohort confirmed the predictive ability of PTAAMG-Sig in the clinical response to ICIs therapy, which correlated with the infiltration of immune cells (e.g., T lymphocytes and nature killer cells). Corresponding to the concentrations of PFAAs, we discovered that the high PTAAMG-Sig risk score patients showed a significantly lower concentration of plasma-free α-aminobutyric acid.
Conclusion: In patients with LUAD, the PTAAMG-Sig effectively predicted OS, drug sensitivity, and immunotherapy outcomes. These findings are expected to provide new targets and strategies for personalized treatment of LUAD patients.

Keywords: TP53 mutation; amino acid metabolism pathway; lung adenocarcinoma; multi-omics analysis; plasma-free α-aminobutyric acid; prognostic gene signature

DOI: https://doi.org/10.3389/fimmu.2024.1361992

Front Immunol. 2024 ;15 1483182

Anti-PD1 therapies induce an early expansion of Ki67+CD8+ T cells in metastatic non-oncogene addicted NSCLC patients.

Alain Gelibter, Lucrezia Tuosto, Angela Asquino, Marco Siringo, Arianna Sabatini, Ilaria Grazia Zizzari, Angelica Pace, Fabio Scirocchi, Flavio Valentino, Serena Bianchini, Salvatore Caponnetto, Donatella Paoli, Filippo Bellati, Daniele Santini, Marianna Nuti, Aurelia Rughetti, Chiara Napoletano.

Pembrolizumab (an anti-PD1 antibody) alone or combined with chemotherapy represented the standard of care for advanced non-oncogene addicted non-small cell lung cancer (NSCLC) patients. These therapies induced early modifications of the immune response impacting the clinical outcome. Identifying early changes in the immune system was critical to directing the therapeutic choice and improving the clinical outcome. In this study, we aim to analyze the activating and inhibiting immune cells of NSCLC patients before and during therapy to identify patients who will benefit from immunotherapies. Forty-eight NSCLC patients were analyzed before (T0) and after the first cycle of immunotherapy (T1), evaluating several activating (CD137+and PD1+), proliferating (Ki67+) and immunosuppressing immune subsets (Tregs: total, active, resting, and non-suppressive; MDSCs: PMN(Lox1+)-MDSC and M-MDSCs) by cytofluorimetry. Concurrently, 14 soluble immune checkpoints were analyzed by Luminex assay. Immunotherapy significantly increased the levels of Ki67+(total and CD8+) T cells, PMN(Lox1+)-MDSCs, non-suppressive Tregs (nsTregs), and soluble PD1 from T0 to T1 in the entire NSCLC population, while decreased active Tregs. These changes were partially attributed to responding patients who showed an increase of Ki67+ and CD8+T cells and nsTregs at T1. CD137+(total, CD8+, and CD4+) T cells and soluble LAG3 were predictor factors at T0 and T1. A low ratio of Tregs/CD137+ T cells and high levels of Ki67+CD137+ T cells positively correlated with response to therapy at T0 and T1, respectively. Results highlighted that immunotherapy improved the immunological fitness of those patients who benefited from immunotherapy, changing the immunological balance towards immune activation.

Keywords: CD137; NSCLC; anti-PD-1; immune checkpoint inhibitors; lymphocytes

DOI: https://doi.org/10.3389/fimmu.2024.1483182

Lung Cancer. 2024 Dec 09. pii: S0169-5002(24)00585-3. [Epub ahead of print]199 108051

Decoding KRAS mutation in non-small cell lung cancer patients receiving immunotherapy: A retrospective institutional comparison and literature review.

INTRODUCTION: KRAS mutation the most common molecular alteration in advanced non-small cell lung cancer (NSCLC) and is associated with an unfavourable prognosis, largely due to the lack of targeted therapeutic options for the majority of the KRAS mutated isoforms. The landscape of NSCLC treatment has expanded with the introduction of immune checkpoint inhibitors (ICIs). Nonetheless, data regarding the efficacy of ICI in NSCLC patients harbouring KRAS mutations are conflicting. This study aimed to compare clinical outcomes of ICIs in advanced NSCLC with different isoforms of KRAS mutations.
METHODS: A retrospective study was conducted on 143 patients with advanced NSCLC harbouring different KRAS mutation and treated with immune checkpoint inhibitors (ICI) between December 2020 and July 2022 at "Fondazione IRCCS Istituto Nazionale dei Tumori" in Milan. Log-rank and Cox Hazard methods were used for survival analysis.
RESULTS: We evaluated 143 patients with advanced non-small cell lung cancer (NSCLC) harboring KRAS mutations. The most common mutation was G12C (41 %), followed by G12V (23.7 %) and G12D (11.8 %). The G12C mutation was notably associated with a higher incidence of bone metastases (42 %). Immunotherapy was administered as monotherapy in 54.5 % of cases, while 69 % received it as part of a first-line combination with chemotherapy. Co-mutations were detected in 52 % of patients, with Q61 (63 %) and G12C (58 %) being the most prevalent. Among these, 24 % had STK11 co-mutations, and 29 % had TP53 co-mutations. No significant differences in overall survival (OS) or progression-free survival (PFS) were observed across different KRAS subtypes. The longest OS was seen in patients with Q61 (46.5 months), 13X (31.8 months), and G12C (28.7 months). The highest overall response rate (ORR) of 73 % was observed in the G12D group, particularly with the combination of chemoimmunotherapy, where stable disease was the most common outcome at 40 %. The median duration of response (DOR) was 7.4 months across both treatments. The longest DOR was seen in the G12V group at 10.2 months, with no significant difference between treatments. In contrast, the shortest DOR was in the G12A group, with 1.54 months in those treated with combination therapy compared to 2.57 months with single-agent therapy. Regarding co-mutations, patients with STK11 co-mutations had a higher median OS than those without (39.7 vs. 26.1 months), but this was not statistically significant (p = 1). Similarly, TP53 co-mutations were associated with a lower median OS (19.1 vs. 26.1 months, p = 0.7), though this too was not statistically significant. Importantly, bone metastases emerged as a significant adverse prognostic factor, nearly doubling the risk of mortality (HR: 2.81, p < 0.001), regardless of KRAS subtype or co-mutation status.
CONCLUSION: KRAS mutation subtypes demonstrate varying clinical outcomes. Although no statistically significant differences were observed in overall survival (OS) or progression-free survival (PFS), bone metastases were identified as a significant adverse prognostic factor, nearly doubling the risk of mortality (HR: 2.72, p < 0.001) regardless of KRAS subtype or co-mutation status. These findings underscore the importance of personalized treatment approaches tailored to the genetic profiles of patients with advanced NSCLC.

Keywords: Co-mutation; Immunotherapy; KRAS subtype; Non–small cell lung cancer

DOI: https://doi.org/10.1016/j.lungcan.2024.108051

Discov Oncol. 2025 Jan 02. 16(1): 1

Integrated bioinformatics analysis identifies ALDH18A1 as a prognostic hub gene in glutamine metabolism in lung adenocarcinoma.

Hao Ren, Deng-Feng Ge, Zi-Chen Yang, Zhen-Ting Cheng, Shou-Xiang Zhao, Bin Zhang.

Glutamine metabolism is pivotal in cancer biology, profoundly influencing tumor growth, proliferation, and resistance to therapies. Cancer cells often exhibit an elevated dependence on glutamine for essential functions such as energy production, biosynthesis of macromolecules, and maintenance of redox balance. Moreover, altered glutamine metabolism can contribute to the formation of an immune-suppressive tumor microenvironment characterized by reduced immune cell infiltration and activity. In this study on lung adenocarcinoma, we employed consensus clustering and applied 101 types of machine learning methods to systematically identify key genes associated with glutamine metabolism and develop a risk model. This comprehensive approach provided a clearer understanding of how glutamine metabolism associates with cancer progression and patient outcomes. Notably, we constructed a robust nomogram based on clinical information and patient risk scores, which achieved a stable area under the curve (AUC) greater than 0.8 for predicting patient survival across four datasets, demonstrating high predictive accuracy. This nomogram not only enhances our ability to stratify patient risk but also offers potential targets for therapeutic intervention aimed at disrupting glutamine metabolism and sensitizing tumors to existing treatments. Moreover, we identified ALDH18A1 as a prognostic hub gene of glutamine metabolism, characterized by high expression levels in glutamine cluster 3, which is associated with poor clinical outcomes and worse survival, and is included in the risk model. Such insights underscore the critical role of glutamine metabolism in cancer and highlight avenues for personalized medicine in oncology research.

DOI: https://doi.org/10.1007/s12672-024-01698-3

Adv Sci (Weinh). 2024 Dec 30. e2408789

Inhibition of Endoplasmic Reticulum Stress Cooperates with SLC7A11 to Promote Disulfidptosis and Suppress Tumor Growth upon Glucose Limitation.

Jin Wang, Jing Chen, Kexin Fan, Minglin Wang, Min Gao, Yakun Ren, Shaobo Wu, Qian He, Kangsheng Tu, Qiuran Xu, Yilei Zhang.

Disulfidptosis is a newly discovered type of regulated cell death triggered by disulfide bond accumulation and NADPH (nicotinamide adenine dinucleotide phosphate) depletion due to glucose deprivation. However, the regulatory mechanisms involving additional cellular circuits remain unclear. Excessive disulfide bond accumulation can impair endoplasmic reticulum (ER) homeostasis and activate the ER stress response. In this study, we found that SLC7A11-mediated disulfidptosis upon glucose deprivation is accompanied by ER stress induction. Pharmacological inhibition of SLC7A11-mediated cystine uptake or cystine withdrawal not only blocks disulfidptosis under glucose starvation but also suppresses the ER stress response, indicating a close link between these processes. Moreover, inhibitors targeting the ER stress response promote disulfidptosis, while ER stress inducers suppress glucose starvation-induced disulfidptosis in SLC7A11-high-expressing cells, suggesting a protective role for ER stress during disulfidptosis. Similar effects are observed in cells treated with glucose transporter inhibitors (GLUTi). Finally, combined treatment with ER stress inhibitors and GLUTi significantly suppresses tumor growth both in vitro and in vivo by inducing disulfide stress and subsequent disulfidptosis. In summary, these findings reveal a novel role for ER stress in regulating disulfidptosis and provide theoretical insights into the potential application of GLUTi and ER stress inhibitors in cancer therapy.

Keywords: SLC7A11; disulfidptosis; endoplasmic reticulum stress; glucose deprivation; tumor

DOI: https://doi.org/10.1002/advs.202408789