bims-meluca 2024-10-13 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2024–10–13
seven papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge

Immune signatures of patients with advanced non-small-cell lung cancer for efficacy prediction after immunotherapy.
Biomarker role of thyroid irAE and PD-L1 positivity in predicting PD-1 blockade efficacy in patients with non-small cell lung cancer.
PD-1 expression in tumor infiltrating lymphocytes as a prognostic marker in early-stage non-small cell lung cancer.
The Clinical Values of Circulating Tumor Cells and T Lymphocyte Subsets in Predicting a Prognosis of Lung Cancer.
Plasma fatty acid levels and risk of non-small cell lung cancer: a large-scale prospective cohort study.
Leptin as a surrogate immune-metabolic marker to predict impact of anti-cachectic therapy: results of a prospective randomized trial in multiple solid tumors.
Tumor Cell Spatial Organization Directs EGFR/RAS/RAF Pathway Primary Therapy Resistance through YAP Signaling.

Ther Adv Med Oncol. 2024 ;16 17588359241284946

Immune signatures of patients with advanced non-small-cell lung cancer for efficacy prediction after immunotherapy.

Yung-Hung Luo, Chia-I Shen, Chi-Lu Chiang, Yuh-Min Chen.

   Background: Programmed cell death protein 1 ligand 1 (PD-L1) expression alone may not be the optimal predictor of immunotherapy (IO) efficacy in advanced non-small cell lung cancer (NSCLC). Evaluation of circulating immune signatures using mass cytometry is a promising technique for predicting IO response and prognosis. The utility of circulating immune signatures for efficacy prediction after IO in advanced NSCLC remains to be elucidated.
Objectives: To assess the feasibility of circulating immune cells and cytokines in predicting tumor response to IO in advanced NSCLC.
Design: A prospective observational study.
Methods: To investigate dynamic changes in immune signatures, blood specimens were prospectively collected from patients with NSCLC at baseline and following chemotherapy (C/T) and/or IO. Mass cytometry and enzyme-linked immunosorbent assay were used to characterize immune signatures and cytokine patterns to identify correlations between immune profiles and treatment efficacy.
Results: The study enrolled 45 patients. The proportion of circulating natural killer (NK) cells and CD8+ T cells significantly increased after IO alone treatment. Cell levels of PD-1+CD8+ T cells, PD-1+CD4+ T cells, TIM-3+CD8+ T cells, LAG-3+ NK cells, and LAG-3+CD8+ T cells significantly decreased in patients with treatment response to IO alone. Tumor necrosis factor-alpha (TNF-α) levels significantly increased after IO alone treatment. Patients with high PD-1+CD8+ T cells before IO alone treatment had lower overall survival (OS) compared to those with low levels. Patients with high LAG-3+CD8+ T cells before chemotherapy plus immunotherapy treatment had lower OS compared to those with low levels.
Conclusion: Responses to IO in NSCLC were correlated with declines in specific exhausted T cells, suggesting that IO may exert therapeutical efficacy by decreasing circulating exhausted T cells, which were associated with poorer survival, while also increasing TNF-α. These results highlight the prognostic value of monitoring changes in circulating exhausted T cells to predict IO response and survival outcomes in advanced lung cancer.

Keywords:  cytokines; cytometry by time-of-flight (CyTOF); immune signature; immunotherapy; lung cancer

DOI:  https://doi.org/10.1177/17588359241284946
Cancer Immunol Immunother. 2024 Oct 09. 73(12): 260

Biomarker role of thyroid irAE and PD-L1 positivity in predicting PD-1 blockade efficacy in patients with non-small cell lung cancer.

Hye In Kim, Won Gu Kim, Mijin Kim, Nak Gyeong Ko, Mihyeon Jin, Hyun Ae Jung, Jong-Mu Sun, Jin Seok Ahn, Myung-Ju Ahn, Yoon-La Choi, Min Ji Jeon, Tae Yong Kim, Won Bae Kim, Sang-We Kim, Dae Ho Lee, Se Jin Jang, Sun Wook Kim, Jae Hoon Chung, Tae Hyuk Kim, Se-Hoon Lee.

  Thyroid immune-related adverse events (irAEs) are associated with programmed cell death protein 1 (PD-1) blockade efficacy in non-small cell lung cancer (NSCLC). However, their independence from PD-L1 expression and quantitative impact on predicting PD-1 blockade efficacy remain unexplored. This multicenter, retrospective, longitudinal study from Korea included 71 metastatic NSCLC patients who underwent PD-L1 expression and thyroid function testing during PD-1 blockade. Disease progression by the Response Evaluation Criteria for Solid Tumors was the main outcome. Three-stage analyses were performed: (1) multivariate Cox regression models adjusted for PD-L1 expression according to thyroid irAEs; (2) subgroup analyses; (3) regrouping and comparing predictivity of current and alternative staging. Patients with thyroid irAE + exhibited a longer progression-free survival [7/20 vs. 34/51, adjusted HR 0.19 (0.07-0.47); P < 0.001] than those with thyroid irAE-, independent of PD-L1 expression; the results remained across most subgroups without interaction. The three groups showed different adjusted HR for disease progression (Group 1: PD L1 + and thyroid irAE + ; Group 2: PD-L1 + or thyroid irAE + : 5.08 [1.48-17.34]; Group 3: PD-L1- and thyroid irAE- : 30.49 [6.60-140.78]). Alternative staging (Group 1 in stage IVB → stage IVA; Group 3 in stage IVA → stage IVB) improved the prognostic value (PVE: 21.7% vs. 6.44%; C-index: 0.706 vs. 0.617) compared with the 8th Tumor-Node-Metastasis staging. Our study suggests thyroid irAEs and PD-L1 expression are independent biomarkers that improve predicting PD-1 blockade efficacy in NSCLC. Thyroid irAEs would be helpful to identify NSCLC patients who benefit from PD-1 blockade in early course of treatment.

Keywords:  Immune-related adverse event; Non-small cell lung cancer; PD-1 blockade; PD-L1 expression; Predictivity; Thyroid

DOI:  https://doi.org/10.1007/s00262-024-03852-w
Front Oncol. 2024 ;14 1414900

PD-1 expression in tumor infiltrating lymphocytes as a prognostic marker in early-stage non-small cell lung cancer.

Asaf Dan, Ozan Aricak, Konstantinos Rounis, M Angeles Montero-Fernandez, Ricardo Guijarro, Simon Ekman, Cristian Ortiz-Villalón, Luigi De Petris.

   Introduction: Programmed death ligand - 1 (PD-L1) expression is a well-established predictive biomarker for immunotherapy in non-small cell lung cancer (NSCLC). Programmed death - 1 (PD-1) serves as the target protein to PD-L1 and their interaction serves as a crucial pathway for immune evasion. This study aimed to investigate the expression pattern of PD-1 on Tumor-infiltrating lymphocytes (TILs) in early-stage NSCLC, and its potential role as prognostic biomarker.
Materials & methods: PD-1 was evaluated in 474 surgical resected early-stage NSCLC specimens, using Tissue microarray and immunohistochemical staining. Expression was scored as negative (<1%) or positive. Positive PD-1 expression was further divided into low (<10%) and high (≥10%). None of the patients had received treatment with PD-1/PD-L1 inhibitors.
Results: PD-1 expression ≥1% in TILs was observed in 83.5% of cases and was associated with pT stage (p=0.02), grade 3 (p=0.004), and adenocarcinoma subtype (p=0.05). Individuals with high PD-1 expression (≥10%) experienced reduced 10-year overall survival (Log-Rank test = 0.005). In addition, high PD-1 expression emerged as an independent factor associated with reduced survival on multivariate analysis (HR: 1.328 (95% CI: 1.074-1.641).
Conclusions: Patients with early-stage NSCLC who exhibited PD-1 expression of ≥10% on TILs had an unfavorable 10-year OS rate. These findings indicate that elevated PD-1 expression on TILs can be associated with immune evasion during the early stages of malignancy evolution in the NSCLC setting and further research is required to further delineate the role of PD-1/PD-L1 pathway on tumor immune senescence. These results underline the potential role of PD-1/PD-L1 inhibitors in the treatment of early-stage NSCLC.

Keywords:  PD-1; TILs; Tissue microarray; early-stage NSCLC; immunotherapy; prognosis

DOI:  https://doi.org/10.3389/fonc.2024.1414900
Clin Lab. 2024 Oct 01. 70(10):

The Clinical Values of Circulating Tumor Cells and T Lymphocyte Subsets in Predicting a Prognosis of Lung Cancer.

Xi Liu, Xiaosong Yan, Junyu Li, Weimin Mao, Feng Jiang.

BACKGROUND: Lung cancer is the most lethal cancer in men and women. Recently, it has been reported that circu-lating tumor cells (CTCs) are sensitive and reliable biomarkers for tracing relapse and metastasis of cancer patients. Many studies also showed that immune cellular dysfunctions in lung cancer patients are major reasons for cancer development. In this study, we explored the clinical significance of CTCs and T lymphocyte subtypes in lung cancer patients.
METHODS: A total of 92 patients with diagnosed lung cancer, including 23 squamous-cell carcinoma and 69 adenocarcinoma, were enrolled in this study. Another 10 patients with non-carcinoma nodules in their lungs were also recruited as a control group. Peripheral blood samples were drawn from the patients with lung cancer and from the control cases before the treatment. The identification of CTCs was carried out by a PatrolCTC detection method. The T lymphocyte subtypes were characterized by flow cytometry (FACS). Cytokines interleukin-2 (IL-2), interleukin-4 (IL-4), interleukin-17A (IL-17A), interleukin-10 (IL-10), and interferon  (IFN-) were detected by meso scale discovery (MSD) assay.
RESULTS: Out of the enrolled patients, 69 (75%) patients with non-small cell lung cancer (NSCLC) were male and 23 (25 %) were female. Smoking and non-smoking history was 50% (46 cases) each. The case numbers for I - IV tumor-node-metastasis (TNM) stages were 23 (25.0%), 28 (30.4%), 16 (17.4%), and 25 (27.2%), respectively. The positive rates of the CTCs before treatment were 8.7% (2/23), 17.6% (5/28), 81.3% (13/16), and 100% (25/25) in stage I, II, III, and IV patients, respectively. Total CTCs, mixed CTCs, and mesenchymal CTCs (MCTCs) were strongly related to the progression-free survival (PFS) of the patients. In addition, total CTCs (≥ 6) and positive MCTCs also significantly correlated with recurrence and metastasis. The patients with high CTCs also had low levels of CD4, CD4/CD8 ratio, IL-2, and IFN. In contrast, IL-10 in high CTCs patients was significant elevated. These results indicate that the CTC numbers in lung cancer patients are an independent indicator for a worse PFS.
CONCLUSIONS: Higher total CTCs, mixed CTCs, and MCTCs in peripheral blood were significant biomarkers for predicting the prognosis of lung cancer patients. High CTCs also had a strong correlation with weak cellular immunity functions.

DOI: https://doi.org/10.7754/Clin.Lab.2024.230514
Front Nutr. 2024 ;11 1462300

Plasma fatty acid levels and risk of non-small cell lung cancer: a large-scale prospective cohort study.

Hua-Long Lin, Qiu-Yan Lin, Jie-Ni Feng, Wei-E Zheng, Chuang Yang, Shao-Fei Yuan.

   Background: Non-small cell lung cancer (NSCLC) ranks among the most prevalent and lethal malignancies globally. Fatty acids (FAs) play a significant role in diverse physiological and pathological mechanisms, yet their precise involvement in NSCLC remains poorly understood.
Methods: This study utilized a large-scale prospective cohort of 249,132 participants, observed over an average of 12 years, to investigate the relationship between different FAs and NSCLC risk. Analytical approaches included Cox proportional hazards regression, Kaplan-Meier survival analysis, accelerated failure time (AFT) modeling, and restricted cubic spline (RCS) analysis.
Results: During the follow-up period, 1,460 participants were diagnosed with NSCLC. Cox regression analysis demonstrated that elevated levels of docosahexaenoic acid (DHA), linoleic acid (LA), and omega-3 were inversely associated with NSCLC risk. Kaplan-Meier curves, along with AFT models, corroborated that elevated concentrations of DHA and LA significantly delayed NSCLC onset. Additionally, RCS analysis uncovered nuanced dose-response relationships between these FAs and NSCLC. Stratified analyses highlighted variability based on smoking status, gender, and body mass index subgroups.
Conclusion: The concentration of specific FAs exhibits a significant association with NSCLC risk. These results offer a foundation for devising dietary FA composition adjustments aimed at reducing NSCLC risk.

Keywords:  UK Biobank; cancer prevention; fatty acids; non-small cell lung cancer; prospective cohort study

DOI:  https://doi.org/10.3389/fnut.2024.1462300
ESMO Open. 2024 Oct 09. pii: S2059-7029(24)01508-4. [Epub ahead of print]9(10): 103738

Leptin as a surrogate immune-metabolic marker to predict impact of anti-cachectic therapy: results of a prospective randomized trial in multiple solid tumors.

C Madeddu, G Gramignano, E Lai, G Pinna, L Tanca, M C Cherchi, C Floris, D Farci, A Pretta, M Scartozzi, A Macciò.

   DESCRIPTION OF THE WORK: Leptin is a reliable predictive and surrogate marker of the efficacy of multitargeted treatment of cancer cachexia.
PURPOSE: To the best of our knowledge, no study has assessed the predictive role of biomarkers in establishing the effectiveness of anti-cachectic treatment, which remains a complex issue. Herein, we aimed to find a marker that can detect early response to anti-cachectic treatment.
PATIENTS AND METHODS: From January 2012 to December 2022, all consecutive eligible advanced cancer patients with cachexia were prospectively enrolled in an exploratory and validation cohort according to eligibility criteria. All patients received a combined anti-cachectic treatment consisting of megestrol acetate plus celecoxib plus l-carnitine plus antioxidants that showed efficacy in a previous phase III randomized study. Primary endpoints were an increase in lean body mass (LBM), a decrease in resting energy expenditure (REE), a decrease in fatigue, and improvement in global quality of life.
RESULTS: A total of 553 consecutive patients were recruited. Twenty patients dropped out, equally distributed over the exploratory (11 patients) and validation (9 patients) cohorts, for early death due to disease progression. Then, 533 patients were deemed assessable. Leptin level changes inversely correlated with circulating levels of inflammatory mediators and reflected the improvement of body composition, energy metabolism, functional performance, and quality of life. At multivariate regression analysis, at week 8, leptin change was an independent predictor of LBM, skeletal muscle index (SMI), grip strength increase, and REE; at week 16, leptin change was an independent predictor of the same parameters and improvement in Eastern Cooperative Oncology Group performance status. The ability of leptin to predict changes in LBM, SMI, REE, and grip strength was superior to that of other inflammatory markers when comparing the receiver operating curves. Moreover, increasing delta leptin values were associated with significantly better outcomes in LBM, SMI, REE, grip strength, and fatigue.
CONCLUSIONS: Leptin is a reliable predictive marker for multitargeted anti-cachectic treatment outcomes. Thus, it can be an ideal candidate for monitoring and predicting the effects of anti-cachectic treatment and a surrogate marker of the immune-metabolic actions of the selected drugs.

Keywords:  cachexia; combined approach; inflammation; leptin; quality of life; sarcopenia

DOI:  https://doi.org/10.1016/j.esmoop.2024.103738
bioRxiv. 2024 Sep 28. pii: 2024.09.26.615226. [Epub ahead of print]

Tumor Cell Spatial Organization Directs EGFR/RAS/RAF Pathway Primary Therapy Resistance through YAP Signaling.

Rachel Nakagawa, Andrew Beardsley, Sophia Durney, Mary-Kate Hayward, Vishvak Subramanyam, Nathaniel P Meyer, Harrison Wismer, Hani Goodarzi, Valerie M Weaver, Daniel Van de Mark, Andrei Goga.

Non-small cell lung cancers (NSCLC) harboring common mutations in EGFR and KRAS characteristically respond transiently to targeted therapies against those mutations, but invariably, tumors recur and progress. Resistance often emerges through mutations in the therapeutic target or activation of alternative signaling pathways. Mechanisms of acute tumor cell resistance to initial EGFR (EGFRi) or KRAS G12C (G12Ci) pathway inhibition remain poorly understood. Our study reveals that acute response to EGFR/RAS/RAF-pathway inhibition is spatial and culture context specific. In vivo, EGFR mutant tumor xenografts shrink by > 90% following acute EGFRi therapy, and residual tumor cells are associated with dense stroma and have increased nuclear YAP. Interestingly, in vitro EGFRi induced cell cycle arrest in NSCLC cells grown in monolayer, while 3D spheroids preferentially die upon inhibitor treatment. We find differential YAP nuclear localization and activity, driven by the distinct culture conditions, as a common resistance mechanism for selective EGFR/KRAS/BRAF pathway therapies. Forced expression of the YAP S127A mutant partially protects cells from EGFR-mediated cell death in spheroid culture. These studies identify YAP activation in monolayer culture as a non-genetic mechanism of acute EGFR/KRAS/BRAF therapy resistance, highlighting that monolayer vs spheroid cell culture systems can model distinct stages of patient cancer progression.

DOI: https://doi.org/10.1101/2024.09.26.615226