bims-meluca 2023-04-30 papers

Cancer Immunol Immunother. 2023 Apr 26.

Cytokine profiling identifies circulating IL-6 and IL-15 as prognostic stratifiers in patients with non-small cell lung cancer receiving anti-PD-1/PD-L1 blockade therapy.

Yusuke Inoue, Naoki Inui, Masato Karayama, Kazuhiro Asada, Masato Fujii, Shun Matsuura, Tomohiro Uto, Dai Hashimoto, Takashi Matsui, Masaki Ikeda, Hideki Yasui, Hironao Hozumi, Yuzo Suzuki, Kazuki Furuhashi, Noriyuki Enomoto, Tomoyuki Fujisawa, Takafumi Suda.

Whether circulating levels of specific cytokines at baseline link with treatment efficacy of immune checkpoint blockade (ICB) therapy in patients with non-small cell lung cancer remains unknown. In this study, serum samples were collected in two independent, prospective, multicenter cohorts before the initiation of ICB. Twenty cytokines were quantified, and cutoff values were determined by receiver operating characteristic analyses to predict non-durable benefit. The associations of each dichotomized cytokine status with survival outcomes were assessed. In the discovery cohort (atezolizumab cohort; N = 81), there were significant differences in progression-free survival (PFS) in accordance with the levels of IL-6 (log-rank test, P = 0.0014), IL-15 (P = 0.00011), MCP-1 (P = 0.013), MIP-1β (P = 0.0035), and PDGF-AB/BB (P = 0.016). Of these, levels of IL-6 and IL-15 were also significantly prognostic in the validation cohort (nivolumab cohort, N = 139) for PFS (log-rank test, P = 0.011 for IL-6 and P = 0.00065 for IL-15) and overall survival (OS; P = 3.3E-6 for IL-6 and P = 0.0022 for IL-15). In the merged cohort, IL-6high and IL-15high were identified as independent unfavorable prognostic factors for PFS and OS. The combined IL-6 and IL-15 status stratified patient survival outcomes into three distinct groups for both PFS and OS. In conclusion, combined assessment of circulating IL-6 and IL-15 levels at baseline provides valuable information to stratify the clinical outcome of patients with non-small cell lung cancer treated with ICB. Further studies are required to decipher the mechanistic basis of this finding.

Keywords: Cytokine; IL-15; IL-6; Immune checkpoint inhibitor; Non-small cell lung cancer; Prognostic factor

DOI: https://doi.org/10.1007/s00262-023-03453-z

Eur J Med Res. 2023 Apr 26. 28(1): 158

Genetic associations between circulating metabolic biomarkers and lung cancer in East Asians and Europeans.

Kai Liu, Shangshang Wang, Yuhan Zhou, Sha Huang, Yifan Liu, Lijiang Song, Zhengfu He.

BACKGROUND: Metabolic biomarkers are reported to be associated with the risk of lung cancer (LC). However, the observed associations from epidemiological studies are either inconsistent or inconclusive.
METHODS: The genetic summary data of high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL), total cholesterol (TC), triglyceride (TG), fasting plasma glucose (FPG), and glycated hemoglobin (HbA1c) and those of the LC and its histological subtypes were retrieved from previous GWASs. We performed two-sample Mendelian randomization (MR) and multivariable MR analyses to examine the associations between genetically predicted metabolic biomarkers and LC in East Asians and Europeans.
RESULTS: In East Asians, the inverse-variance weighted (IVW) method suggests that LDL (odds ratio [OR] = 0.799, 95% CI 0.712-0.897), TC (OR = 0.713, 95% CI 0.638-0.797), and TG (OR = 0.702, 95% CI 0.613-0.804) were significantly associated with LC after correction for multiple testing. For the remaining three biomarkers, we did not detect significant association with LC by any MR method. Multivariable MR (MVMR) analysis yielded an OR of 0.958 (95% CI 0.748-1.172) for HDL, 0.839 (95% CI 0.738-0.931) for LDL, 0.942 (95% CI 0.742-1.133) for TC, 1.161 (95% CI 1.070-1.252) for TG, 1.079 (95% CI 0.851-1.219) for FPG, and 1.101 (95% CI 0.922-1.191) for HbA1c. In Europeans, the univariate MR analyses did not detect significant association between exposures and outcomes. However, in MVMR analysis integrating circulating lipids and lifestyle risk factors (smoking, alcohol drinking, and body mass index), we found that TG was positively associated with LC in Europeans (OR = 1.660, 95% CI 1.060-2.260). Subgroup and sensitivity analysis yielded similar results to the main analyses.
CONCLUSIONS: Our study provides genetic evidence that circulating levels of LDL was negatively associated with LC in East Asians, whereas TG was positively associated with LC in both populations.

Keywords: LDL; Lung cancer; Mendelian randomization; Metabolic biomarkers; Triglyceride

DOI: https://doi.org/10.1186/s40001-023-01116-4

JCI Insight. 2023 Apr 24. pii: e165419. [Epub ahead of print]8(8):

Tumor loss-of-function mutations in STK11/LKB1 induce cachexia.

Cancer cachexia (CC), a wasting syndrome of muscle and adipose tissue resulting in weight loss, is observed in 50% of patients with solid tumors. Management of CC is limited by the absence of biomarkers and knowledge of molecules that drive its phenotype. To identify such molecules, we injected 54 human non-small cell lung cancer (NSCLC) lines into immunodeficient mice, 17 of which produced an unambiguous phenotype of cachexia or non-cachexia. Whole-exome sequencing revealed that 8 of 10 cachexia lines, but none of the non-cachexia lines, possessed mutations in serine/threonine kinase 11 (STK11/LKB1), a regulator of nutrient sensor AMPK. Silencing of STK11/LKB1 in human NSCLC and murine colorectal carcinoma lines conferred a cachexia phenotype after cell transplantation into immunodeficient (human NSCLC) and immunocompetent (murine colorectal carcinoma) models. This host wasting was associated with an alteration in the immune cell repertoire of the tumor microenvironments that led to increases in local mRNA expression and serum levels of CC-associated cytokines. Mutational analysis of circulating tumor DNA from patients with NSCLC identified 89% concordance between STK11/LKB1 mutations and weight loss at cancer diagnosis. The current data provide evidence that tumor STK11/LKB1 loss of function is a driver of CC, simultaneously serving as a genetic biomarker for this wasting syndrome.

Keywords: Genetic variation; Lung cancer; Metabolism; Molecular genetics; Oncology

DOI: https://doi.org/10.1172/jci.insight.165419

Support Care Cancer. 2023 Apr 28. 31(5): 308

Significance of localized expression of full-length growth differentiation factor-15 in cachexia of advanced non-small cell lung cancer.

Satomi Morita-Tanaka, Aya Miyagawa-Hayashino, Tadaaki Yamada, Yohei Matsui, Kenji Morimoto, Osamu Hiranuma, Naoko Masuzawa, Akihiro Yoshimura, Masahiro Iwasaku, Shinsaku Tokuda, Yoshiko Kaneko, Young Hak Kim, Eiichi Konishi, Koichi Takayama.

PURPOSE: Growth differentiation factor-15 (GDF-15) is one of the key cachexia-inducing factors. Clinical trials on therapies targeting GDF-15 for cancer and cancer cachexia are underway. While the role of circulating GDF-15 in cachexia has been clarified, the effects of GDF-15 expression within cancer cells remain to be fully elucidated. Hence, the objective of this study was to investigate the expression of GDF-15 in advanced lung cancer tissues and to understand its role in cachexia.
METHODS: We retrospectively examined the expression level of full-length GDF-15 in advanced non-small cell lung cancer tissues and analyzed the relationship between the staining intensity and clinical data in 53 samples.
RESULTS: We found that 52.8% of the total samples were GDF-15 positive, and GDF-15 expression significantly correlated with improved C-reactive protein/albumin ratio (p = 0.008). It did not correlate with the existence of cancer cachexia and overall survival (p = 0.43).
CONCLUSION: Our findings show that GDF-15 expression significantly correlated with improved C-reactive protein/albumin ratio, but not the existence of cancer cachexia in advanced NSCLC patients.

Keywords: Advanced non-small cell lung carcinoma; C-reactive protein/albumin ratio; Growth differentiation factor-15; Immunohistochemistry

DOI: https://doi.org/10.1007/s00520-023-07771-x

Biomed Res Int. 2023 ;2023 4019091

Glycolytic Genes Predict Immune Status and Prognosis Non-Small-Cell Lung Cancer Patients with Radiotherapy and Chemotherapy.

Tianye Zhao, Jingjing Shao, Jia Liu, Yidan Wang, Jia Chen, Song He, Gaoren Wang.

Background: Non-small-cell lung cancer (NSCLC) is a major health problem that endangers human health. The prognosis of radiotherapy or chemotherapy is still unsatisfactory. This study is aimed at investigating the predictive value of glycolysis-related genes (GRGs) on the prognosis of NSCLC patients with radiotherapy or chemotherapy.
Methods: Download the clinical information and RNA data of NSCLC patients receiving radiotherapy or chemotherapy from TCGA and geo databases and obtain GRGs from MsigDB. The two clusters were identified by consistent cluster analysis, the potential mechanism was explored by KEGG and GO enrichment analyses, and the immune status was evaluated by estimate, TIMER, and quanTIseq algorithms. Lasso algorithm is used to build the corresponding prognostic risk model.
Results: Two clusters with different GRG expression were identified. The high-expression subgroup had poor overall survival. The results of KEGG and GO enrichment analyses suggest that the differential genes of the two clusters are mainly reflected in metabolic and immune-related pathways. The risk model constructed with GRGs can effectively predict the prognosis. The nomogram combined with the model and clinical characteristics has good clinical application potential.
Conclusion: In this study, we found that GRGs are associated with tumor immune status and can assess the prognosis of NSCLC patients receiving radiotherapy or chemotherapy.

DOI: https://doi.org/10.1155/2023/4019091

Cancer Biother Radiopharm. 2023 Apr 25.

Can Baseline [18F]FDG PET/CT Predict Response to Immunotherapy After 6 Months and Overall Survival in Patients with Lung Cancer or Malignant Melanoma? A Multicenter Retrospective Study.

Andrea Bianchi, Maria Luisa De Rimini, Rosa Sciuto, Alessio Annovazzi, Silvia Di Traglia, Matteo Bauckneht, Francesco Lanfranchi, Silvia Morbelli, Anna Giulia Nappi, Cristina Ferrari, Giuseppe Rubini, Stefano Panareo, Luca Urso, Mirco Bartolomei, Davide D'Arienzo, Tullio Valente, Virginia Rossetti, Paola Caroli, Federica Matteucci, Demetrio Aricò, Michelangelo Bombaci, Domenica Caponnetto, Francesco Bertagna, Domenico Albano, Francesco Dondi, Sara Gusella, Alessandro Spimpolo, Cinzia Carriere, Michele Balma, Ambra Buschiazzo, Rosj Gallicchio, Giovanni Storto, Livia Ruffini, Maura Scarlattei, Giorgio Baldari, Anna Rita Cervino, Lea Cuppari, Marta Burei, Giuseppe Trifirò, Elisabetta Brugola, Carolina Arianna Zanini, Alessandra Alessi, Valentina Fuoco, Ettore Seregni, Désirée Deandreis, Virginia Liberini, Antonino Maria Moreci, Salvatore Ialuna, Sabina Pulizzi, Laura Evangelista.

Aim: To assess the role of baseline 18F-fluorodeoxyglucose ([18F]FDG)-positron emission tomography/computed tomography (PET/CT) in predicting response to immunotherapy after 6 months and overall survival (OS) in patients with lung cancer (LC) or malignant melanoma (MM). Methods: Data from a multicenter, retrospective study conducted between March and November 2021 were analyzed. Patients >18 years old with a confirmed diagnosis of LC or MM, who underwent a baseline [18F]FDG-PET/CT within 1-2 months before starting immunotherapy and had a follow-up of at least 12 months were included. PET scans were examined visually and semiquantitatively by physicians at peripheral centers. The metabolic tumor burden (number of lesions with [18F]FDG-uptake) and other parameters were recorded. Clinical response was assessed at 3 and 6 months after starting immunotherapy, and OS was calculated as the time elapsing between the PET scan and death or latest follow-up. Results: The study concerned 177 patients with LC and 101 with MM. Baseline PET/CT was positive in primary or local recurrent lesions in 78.5% and 9.9% of cases, in local/distant lymph nodes in 71.8% and 36.6%, in distant metastases in 58.8% and 84%, respectively, in LC and in MM patients. Among patients with LC, [18F]FDG-uptake in primary/recurrent lung lesions was more often associated with no clinical response to immunotherapy after 6 months than in cases without any tracer uptake. After a mean 21 months, 46.5% of patients with LC and 37.1% with MM had died. A significant correlation emerged between the site/number of [18F]FDG foci and death among patients with LC, but not among those with MM. Conclusions: In patients with LC who are candidates for immunotherapy, baseline [18F]FDG-PET/CT can help to predict response to this therapy after 6 months, and to identify those with a poor prognosis based on their metabolic parameters. For patients with MM, there was only a weak correlation between baseline PET/CT parameters, response to therapy, and survival.

Keywords: FDG PET/CT; immunotherapy; lung cancer; malignant melanoma; prognosis

DOI: https://doi.org/10.1089/cbr.2022.0092