bims-meluca 2024-03-17 papers

Front Cell Dev Biol. 2023 ;11 1324898

Circulating IL-6 and not its circulating signaling components sIL-6R and sgp130 demonstrate clinical significance in NSCLC patients treated with immune checkpoint inhibitors.

Yoshiro Nakahara, Taku Kouro, Satoru Motoyama, Masatomo Miura, Kazuma Fujita, Yuka Igarashi, Naoko Higashijima, Norikazu Matsuo, Hidetomo Himuro, Feifei Wei, Shun Horaguchi, Kayoko Tsuji, Yasunobu Mano, Mitsuru Komahashi, Haruhiro Saito, Koichi Azuma, Tetsuro Sasada.

Introduction: Clinical roles of plasma IL-6 levels have been reported in patients with various cancers, including non-small cell lung cancer (NSCLC), treated with immune checkpoint inhibitors (ICIs). However, the roles of other IL-6 signaling components, soluble IL-6 receptor (sIL-6R) and soluble gp130 (sgp130), in the plasma have not been elucidated. Methods: Blood was collected from 106 patients with NSCLC before initiation of ICI treatment (anti-PD-1 or anti-PD-L1 antibody). Plasma levels of IL-6, sIL-6R, sgp130, and their complexes were assessed by Cox regression hazard model to evaluate their clinical significance. The clinical role of IL-6 or IL-6R genetic polymorphisms was also analyzed. Results: Cox regression analysis showed that higher plasma IL-6 levels significantly predicted unfavorable overall survival (OS; hazard ratio [HR] 1.34, 95% confidence interval [CI] 1.05-1.68, p = 0.012) in NSCLC patients treated with ICIs. However, plasma sIL-6R and sgp130 levels showed no prognostic significance (p = 0.882 and p = 0.934, respectively). In addition, the estimated concentrations of binary IL-6:sIL-6R and ternary IL-6:sIL-6R:sgp130 complexes and their ratios (binary/ternary complex) were not significantly associated with OS (p = 0.647, p = 0.727, and p = 0.273, respectively). Furthermore, the genetic polymorphisms of IL-6 (-634G>C) and IL-6R (48892A>C) showed no clinical role by Kaplan-Meier survival analysis (p = 0.908 and p = 0.639, respectively). Discussion: These findings demonstrated the clinical significance of plasma levels of IL-6, but not of other IL-6 signaling components, sIL-6R and sgp130, suggesting that classical IL-6 signaling, but not trans-signaling, may be related to anti-tumor immune responses in cancer patients treated with ICIs.

Keywords: IL-6; PD-1; PD-L1; immune checkpoint inhibitor; non-small cell lung cancer (NSCLC); soluble IL-6 receptor (sIL-6R); soluble glycoprotein 130 (sgp130)

DOI: https://doi.org/10.3389/fcell.2023.1324898

Front Immunol. 2024 ;15 1364473

Biological insights from plasma proteomics of non-small cell lung cancer patients treated with immunotherapy.

Introduction: Immune checkpoint inhibitors have made a paradigm shift in the treatment of non-small cell lung cancer (NSCLC). However, clinical response varies widely and robust predictive biomarkers for patient stratification are lacking. Here, we characterize early on-treatment proteomic changes in blood plasma to gain a better understanding of treatment response and resistance.
Methods: Pre-treatment (T0) and on-treatment (T1) plasma samples were collected from 225 NSCLC patients receiving PD-1/PD-L1 inhibitor-based regimens. Plasma was profiled using aptamer-based technology to quantify approximately 7000 plasma proteins per sample. Proteins displaying significant fold changes (T1:T0) were analyzed further to identify associations with clinical outcomes using clinical benefit and overall survival as endpoints. Bioinformatic analyses of upregulated proteins were performed to determine potential cell origins and enriched biological processes.
Results: The levels of 142 proteins were significantly increased in the plasma of NSCLC patients following ICI-based treatments. Soluble PD-1 exhibited the highest increase, with a positive correlation to tumor PD-L1 status, and, in the ICI monotherapy dataset, an association with improved overall survival. Bioinformatic analysis of the ICI monotherapy dataset revealed a set of 30 upregulated proteins that formed a single, highly interconnected network, including CD8A connected to ten other proteins, suggestive of T cell activation during ICI treatment. Notably, the T cell-related network was detected regardless of clinical benefit. Lastly, circulating proteins of alveolar origin were identified as potential biomarkers of limited clinical benefit, possibly due to a link with cellular stress and lung damage.
Conclusions: Our study provides insights into the biological processes activated during ICI-based therapy, highlighting the potential of plasma proteomics to identify mechanisms of therapy resistance and biomarkers for outcome.

Keywords: NSCLC; PD-1; PD-L1; biological process; proteomics

DOI: https://doi.org/10.3389/fimmu.2024.1364473

J Immunother Cancer. 2024 Mar 13. pii: e008480. [Epub ahead of print]12(3):

Efficacy, safety, and biomarker analyses of bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, in patients with advanced non-small cell lung cancer.

Arun Rajan, Houssein Abdul Sater, Osama Rahma, Richy Agajanian, Wiem Lassoued, Jennifer L Marté, Yo-Ting Tsai, Renee N Donahue, Elizabeth Lamping, Shania Bailey, Andrew Weisman, Beatriz Walter-Rodriguez, Rena Ito, Yulia Vugmeyster, Masashi Sato, Andreas Machl, Jeffrey Schlom, James L Gulley.

BACKGROUND: Bintrafusp alfa, a first-in-class bifunctional fusion protein targeting transforming growth factor-β (TGF-β) and programmed cell death ligand 1, has demonstrated encouraging efficacy as second-line treatment in patients with non-small cell lung cancer (NSCLC) in a dose expansion cohort of the phase 1, open-label clinical trial (NCT02517398). Here, we report the safety, efficacy, and biomarker analysis of bintrafusp alfa in a second expansion cohort of the same trial (biomarker cohort).
METHODS: Patients with stage IIIb/IV NSCLC who were either immune checkpoint inhibitor (ICI)-naïve (n=18) or ICI-experienced (n=23) were enrolled. The primary endpoint was the best overall response. Paired biopsies (n=9/41) and peripheral blood (n=14/41) pretreatment and on-treatment were studied to determine the immunological effects of treatment and for associations with clinical activity.
RESULTS: Per independent review committee assessment, objective responses were observed in the ICI-naïve group (overall response rate, 27.8%). No new or unexpected safety signals were identified. Circulating TGF-β levels were reduced (>97%; p<0.001) 2 weeks after initiation of treatment with bintrafusp alfa and remained reduced up to 12 weeks. Increases in lymphocytes and tumor-associated macrophages (TAMs) were observed in on-treatment biospies, with an increase in the M2 (tumor trophic TAMs)/M1 (inflammatory TAMs) ratio associated with poor outcomes. Specific peripheral immune analytes at baseline and early changes after treatment were associated with clinical response.
CONCLUSIONS: Bintrafusp alfa was observed to have modest clinical activity and manageable safety, and was associated with notable immunologic changes involving modulation of the tumor immune microenvironment in patients with advanced NSCLC.

Keywords: clinical trials as topic; immune checkpoint inhibitors; immunotherapy; non-small cell lung cancer; tumor microenvironment

DOI: https://doi.org/10.1136/jitc-2023-008480

Heliyon. 2024 Mar 15. 10(5): e27282

Predictive impact of sarcopenia in advanced non-small cell lung cancer patients treated with immune checkpoint inhibitors: A retrospective study.

Ying Feng, Liyu Wang, Fen Guo, Fan Zhu, Jianming Shi, Yan Wang, Yingru Zhang, Xiaofeng Chen, Luyao Zhang.

Background: Sarcopenia, characterised by an ongoing loss of skeletal muscle mass and reduced strength and function, is frequently observed in patients with non-small cell lung cancer (NSCLC). However, the relationship between sarcopenia and the prognosis of NSCLC treated with immune checkpoint inhibitors (ICIs) remains unclear. This aimed to assess whether sarcopenia is an independent prognostic factor for survival in patients with advanced NSCLC receiving ICIs.
Methods: For this retrospective cohort study, we analysed the medical records of patients attending our hospital aged 18-75 years who were newly diagnosed with stage IIIB to stage IV NSCLC, and who had received ICIs as first- or second-line therapy between May 2019 and April 2022. The skeletal muscle index (SMI) was calculated from computed tomography (CT) images and relevant clinical characteristics within 4 weeks of initiating treatment and used to diagnose sarcopenia status. The Kaplan-Meier method and log-rank test were used to calculate and compare patients' progression-free survival (PFS). Cox proportional hazard regression was used to examine the associations between sarcopenia and survival outcomes. The chi-square test was used to compare treatment response outcomes, such as the objective response rate (ORR), disease control rate (DCR), and immunotherapy-related adverse events (irAEs), between individuals with and without sarcopenia. Additionally, the Student's t-test was utilised to compare SMI values between patients by their objective response (OR) and disease control (DC). Finally, the Mann-Whitney U test was used to compare nutritional and inflammatory indicators between the sarcopenia groups.
Results: The study enrolled 70 patients, of whom 34 (48.6%) were diagnosed with sarcopenia. The median PFS of patients with and without sarcopenia was 7.5 vs. 13.4 months, respectively (p = 0.006). The proportional hazards regression analysis showed sarcopenia to be an independent prognostic factor for shorter PFS (hazard ratio (HR): 0.504, 95% CI: 0.265-0.962, p = 0.038). Using chi square tests, we found significant differences in the ORR (20.59% vs. 58.33%, p = 0.001) and occurrence of any irAEs (44.1% vs. 22.2%, p = 0.028) between the sarcopenia and the non-sarcopenia groups, respectively. The Student's t-test showed a significant difference in SMI between the ORR group and the non-ORR group (49.99 ± 7.00 vs. 42.98 ± 2.18 cm2/m2, p = 0.0015). While the sarcopenia group were with significantly a lower CD4+/CD8+ ratios and a higher C-reactive protein (CRP) level (p = 0.026, p = 0.011, respectively). Conclusions: This study found that sarcopenia is a significant predictor of a poor prognosis for patients with advanced NSCLC receiving ICIs. Multiple inflammatory and immune functions related to prognosis also differ by sarcopenia status.

Keywords: Immune-checkpoint inhibitor; Immune-related adverse events (irAEs); Non-small cell lung cancer (NSCLC); Progression free survival (PFS); Sarcopenia; Skeletal muscle index (SMI)

DOI: https://doi.org/10.1016/j.heliyon.2024.e27282

Transl Cancer Res. 2024 Feb 29. 13(2): 525-541

A novel gene signature related to fatty acid metabolism predicts prognosis, immune landscape, and drug sensitivity in early-stage lung squamous cell carcinoma.

Juqing Xu, Maoran Yu, Weifei Fan, Jifeng Feng.

Background: Dysregulation of fatty acid metabolism (FAM) represents a significant metabolic alteration in tumorigenesis. However, the role of FAM-related genes (FAMRGs) in early-stage lung squamous cell carcinoma (LUSC) remains incompletely understood.
Methods: A series of bioinformatic analyses and machine learning strategies were performed to construct a FAMRGs-based signature to predict prognosis and guide personalized treatment for early-stage LUSC patients. FAMRGs were screened through the Kyoto Encyclopedia of Genes and Genomes (KEGG) database and the Molecular Signature Database (MSigDB). Prognosis FAMRGs were identified using univariate Cox regression, and unsupervised clustering analysis facilitated the division of the cohort into different clusters. The least absolute shrinkage and selection operator (LASSO)-Cox regression and multivariate regression analysis were employed to develop a FAMRGs-based signature for predicting overall survival (OS). A nomogram was subsequently constructed to facilitate risk assessment for individual patients. Comprehensive analyses of metabolic pathways, immune infiltration, immunomodulators, and potentially applicable drugs were conducted across different FAMRGs-related risk groups.
Results: The FAMRGs-based signature, comprising nine genes (ACOT11, APOH, BMX, CYP2R1, DPEP3, FABP6, FADS2, GLYATL2, and THRSP), demonstrated robust predictive capabilities for prognosis in The Cancer Genome Atlas (TCGA)-LUSC dataset and validated across six independent Gene Expression Omnibus (GEO)-LUSC datasets. Notably, the FAMRGs-base signature exhibited superior prognostic capacity and accurate survival prediction compared to conventional clinicopathological features. Furthermore, the signature was closely associated with immune cell infiltration, human leukocyte antigen (HLA) genes, and immune checkpoint genes expression. Additionally, the signature demonstrated potential sensitivity to chemo-/target-therapy.
Conclusions: The FAMRGs-based signature demonstrated superior sensitivity in predicting the prognosis of early-stage LUSC. Detecting FAMRGs may provide predictive targets for the development of clinical treatment strategies.

Keywords: Fatty acid metabolism (FAM); immune infiltration; lung squamous cell carcinoma (LUSC); prognosis signature

DOI: https://doi.org/10.21037/tcr-23-1640

Aging (Albany NY). 2024 Mar 11. 16

Cancer cachexia reduces the efficacy of immune checkpoint inhibitors in cancer patients.

Yean Yu, Li Yan, Tianhui Huang, Zhenfu Wu, Juan Liu.

OBJECTIVE: Cachexia, a multifactorial syndrome, is frequently noticed in cancer patients. A recent study has shown inconsistent findings about the relationship between cachexia and the efficiency of immune checkpoint inhibitors (ICIs). To analyze this disparity, we did a meta-analysis.
METHODS: From the beginning of each database to July 2023, literature describing the association between cachexia and prognosis of ICI-treated patients with solid malignancies was systematically searched in three online databases. Estimates were pooled, and 95% confidence intervals (CIs) were generated.
RESULTS: We analyzed a total of 12 articles, which included data from 1407 patients. The combined results of our analysis showed that cancer patients with cachexia had significantly worse overall survival (HR = 1.88, 95% CI: 1.59-2.22, p < 0.001), progression-free survival (HR = 1.84, 95% CI: 1.59-2.12, p < 0.001), and time to treatment failure (HR = 2.15, 95% CI: 1.32-3.50, p = 0.002). These findings were consistent in both univariate and multivariate analyses. Additionally, while not statistically significant, we observed a trend towards a lower objective response rate in cancer patients with cachexia compared to those without cachexia (OR = 0.59, 95% CI: 0.32-1.09, p = 0.093).
CONCLUSION: Poor survival in cachexia patients suggests a negative relationship between cachexia and ICI efficacy. In clinical practice, the existence of cachexia should be estimated to choose individuals who may benefit from ICIs.

Keywords: cachexia; cancers; immune checkpoint inhibitors; non-small cell lung cancer

DOI: https://doi.org/10.18632/aging.205652