bims-meluca 2024-06-02 papers

Front Pharmacol. 2024 ;15 1384733

Lysosomal degradation of PD-L1 is associated with immune-related adverse events during anti-PD-L1 immunotherapy in NSCLC patients.

Takeru Kashiwada, Ryotaro Takano, Fumihiko Ando, Shoko Kuroda, Yoshishige Miyabe, Ryuji Owada, Akihiko Miyanaga, Tomoko Asatsuma-Okumura, Masaaki Hashiguchi, Yoshikazu Kanazawa, Hiroshi Yoshida, Masahiro Seike, Akihiko Gemma, Yoshiko Iwai.

Background: Immune checkpoint inhibitors (ICIs) can induce immune-related adverse events (irAEs). Liquid biomarkers to predict irAE occurrence are urgently needed. We previously developed an ELISA system to specifically detect soluble PD-L1 (sPD-L1) with PD-1-binding capacity (bsPD-L1). Here, we investigated the relationship between sPD-L1 and bsPD-L1 in gastric cancer (GC) and non-small cell lung cancer (NSCLC) treated with PD-1/PD-L1 blockade and their association with irAEs. Methods: We examined sPD-L1, bsPD-L1, matrix metalloproteinases (MMPs), and proinflammatory cytokine levels by ELISA in plasma samples from 117 GC patients prior to surgery and 72 NSCLC patients prior to and at 2 months after ICI treatment (anti-PD-1, n = 48; anti-PD-L1, n = 24). In mice treated with anti-PD-1/PD-L1 antibodies (Abs), sPD-L1 levels and localization of Abs were examined by ELISA and immunohistochemistry, respectively. Results:sPD-L1 was detected with higher frequency in GC patients than in NSCLC patients, whereas bsPD-L1 was detected with similar frequencies in GC and NSCLC patients. sPD-L1 levels were correlated with IL-1α, IL-1β, TNF-α, and IL-6 levels, while bsPD-L1 levels were correlated with MMP13, MMP3, and IFN-γ levels. In NSCLC patients, anti-PD-L1, but not anti-PD-1, treatment increased sPD-L1, which was associated with irAE development, but not with clinical outcomes. In mice, trafficking of anti-PD-L1 Abs to lysosomes in F4/80+ macrophages resulted in sPD-L1 production, which was suppressed by treatment with lysosomal degradation inhibitor chloroquine and macrophage depletion. Conclusion: Anti-PD-L1-mediated lysosomal degradation induces sPD-L1 production, which can serve as an indicator to predict irAE development during anti-PD-L1 treatment.

Keywords: immune-related adverse event; inflammation; lysosomal degradation; macrophage; soluble PD-L1

DOI: https://doi.org/10.3389/fphar.2024.1384733

Cancer Med. 2024 Jun;13(11): e7241

Effect of body mass index and cholesterol-rich apolipoprotein-B-containing lipoproteins on clinical outcome in NSCLC patients treated with immune checkpoint inhibitors-based therapy: A retrospective analysis.

Zixin Hu, Yumin Zheng, Jiabin Zheng, Yan Wang, Jiangquan Liao, Zhening Liu, Jia Li, Huijuan Cui.

OBJECTIVES: Obesity and hypercholesterolemia are linked to unfavor clinical outcomes. Recent studies declared the paradox that high body mass index (BMI) and serum cholesterol were independently connected to better clinical outcome of immune checkpoint inhibitors (ICIs) monotherapy in non-small cell lung cancer (NSCLC). The aim of the study is to investigate the prognosis of BMI and serum cholesterol in ICIs-based therapy.
METHODS: This is a retrospective study of 95 NSCLC patients treated with ICIs-based therapy at the Department of Oncology and Lung Cancer Center of China-Japan Friendship Hospital. Treatment efficacy was assessed using durable clinical benefit (DCB) versus nondurable benefit (NDB), best response (active vs. nonactive), and progression-free survival (PFS). The prognostic value of BMI, LDL-C, and RC was determined by multivariate regression analyses, while controlling for confounding factors including age, gender, diabetes status, smoking history, and statin usage. BMI was considered a confounding factor in the analysis when examining the impact of lipoproteins.
RESULTS: In our study, we found that in the whole group, BMI ≥25 kg/m2 was linked to a higher risk of poor therapeutic response (OR = 5.92, 95% CI 1.99-19.51, p.val = 0.002) and shorter progression-free survival (HR = 3.00, 95% CI 1.59-5.68, p.val = 0.001). In addition, low levels of RC were associated with better therapeutic response (OR = 0.12, 95% CI 0.02-0.64, p.val = 0.019), while low levels of serum LDL-C were found to predict longer PFS (HR = 0.40, 95% CI 0.19-0.82, p.val = 0.012). These associations were consistent in advanced NSCLC patients receiving ICIs and chemotherapy.
CONCLUSIONS: Our study suggest that BMI ≥25 kg/m2 and elevated levels of apoB-containing lipoproteins, including LDL-C and RC, could potentially serve as useful prognostic markers for predicting poor treatment outcomes in advanced NSCLC patients treated with the combination of chemotherapy and ICIs.

Keywords: body mass index; immune checkpoint inhibitor; low‐density lipoprotein cholesterol; non‐small cell lung cancer; remnant cholesterol

DOI: https://doi.org/10.1002/cam4.7241

Heliyon. 2024 May 30. 10(10): e31399

Role of pyroptosis-related cytokines in the prediction of lung cancer.

Zhouyangfan Peng, Xiqing Tan, Yang Xi, Zi Chen, Yapei Li.

Objectives: Lung cancer is the leading cause to induce cancer-related mortality. Effective biomarkers for prediction the occurrence of lung cancer is urgently needed. Our previous studies indicated that pyroptosis-related cytokines TNF-α, IFN-γ, MIP-1α, MIP-1β, MIP-2 and IP-10 is important to influence the efficacy of chemotherapy drug in lung cancer tissues. But the role of pyroptosis-related cytokines in prediction the occurrence of lung cancer is still unknown.
Methods: Blood samples were collected from 258 lung cancer patients at different stage and 80 healthy volunteers. Serum levels of pyroptosis-related cytokines including TNF-α, IFN-γ, MIP-1α, MIP-1β, MIP-2 and IP-10 were measured by Cytometric Bead Array (CBA). ROC curve was performed to evaluate the cut-off value and diagnosis value for prediction and diagnosis of lung cancer.
Results: Compared with control group, the levels of IP-10, MIP-1α, MIP-1β, MIP-2 and TNF-α were significantly higher in lung cancer patients (45.5 (37.1-56.7): 57.2 (43.0-76.5), 34.4 (21.8-75.2): 115.4 (96.6-191.2), 49.3 (25.6-78.7): 160.5 (124.9-218.6), 22.6 (17.8-31.2): 77.9 (50.1-186.5), 3.80 (2.3-6.2): 10.3 (5.7-16.6)), but the level of IFN-γ was decreased in the patients (12.38 (9.1-27.8): 5.9 (3.5-9.7)). All the above cytokines were significantly associated with the diagnosis of lung cancer, and the AUC values of IFN-γ, IP-10, MIP-1α, MIP-1β, MIP-2, and TNF-α were 0.800, 0.656, 0.905, 0.921, 0.914, and 0.824. And the AUC can rise to 0.986 after combining the above factors, and the sensitivity and specificity also up to 96.7 % and 93.7 %, respectively. Additionally, TNF-α (r = 0.400, P < 0.01), MIP-2 (r = 0.343, P < 0.01), MIP-1α (r = 0.551, P < 0.01) and MIP-1β (r = 0.403, p < 0.01) were positively associated with occurrence of lung cancer, but IFN-γ (r = -0.483, p < 0.01) was negatively associated with occurrence of lung cancer. As far as the potential of early diagnosis of lung cancer, TNF-α (AUC = 0.577), MIP-1α (AUC = 0.804) and MIP-1β (AUC = 0.791) can predict the early stage of lung cancer, and combination of the above three cytokines has a better predictive efficiency (AUC = 0.854).
Conclusion: Our study establishes a link between the levels of IP-10, MIP-1α, MIP-1β, MIP-2, TNF-α and IFN-γ and diagnosis of lung cancer. Besides, we observed a synergistic effect of these five pyroptosis-related cytokines in diagnosing lung cancer patient, suggesting their potential as biomarkers for lung cancer diagnosis. Moreover, the combination of TNF-α, MIP-1α and MIP-1β are also potential predictors for the early diagnosis of lung cancer.

Keywords: Biomarkers; Diagnosis; Lung carcinoma; Pyroptosis-related cytokines

DOI: https://doi.org/10.1016/j.heliyon.2024.e31399

Lung Cancer Manag. 2024 ;13(1): LMT66

Inflammatory parameters in NSCLC with driver mutation.

Mehmet Emin Buyukbayram, Zekeriya Hannarici, Ali Yilmaz, Aykut Turhan, Alperen Akansel Caglar, Pınar Coban Esdur, Mehmet Bilici, Salim Basol Tekin.

Aim: The tumor microenvironment of NSCLC with driver mutations, such as EGFR, ALK and ROS, is less inflammatory. Materials & methods: This retrospective study included 38 patients with NSCLC driver mutations. The relationship between clinical and inflammatory markers concerning progression-free survival and overall survival was analyzed based on Kaplan-Meier curves. Results: The mean age of the patients was 59.8 ± 11.9. Progression-free survival and overall survival were significantly longer in patients under 65 years of age and with low neutrophil-lymphocyte ratio, low systemic immune-inflammation index and high lymphocyte count (p < 0.05). Conclusion: Unlike tumor biology, peripheral inflammatory parameters, such as neutrophil-lymphocyte ratio, systemic immune-inflammation index and lymphocyte count may be associated with survival in NSCLC patients with driver mutations.

Keywords: driver mutation; inflammatory markers; non-small-cell lung cancer; survival

DOI: https://doi.org/10.2217/lmt-2023-0014

Sci Rep. 2024 05 26. 14(1): 12025

Prognostic significance of CT-determined sarcopenia in older patients with advanced squamous cell lung cancer treated with programmed death-1 inhibitors.

Lin Ying, Liqian Xu, Ji Yang, Qin Zhang.

Sarcopenia has been associated with higher toxicity induced by anti-cancer treatments and shorter survival in patients with squamous cell lung carcinoma (SqCLC). Over the past few decades, immune checkpoint inhibitors (ICIs) significantly improves the prognosis. However, few clinical studies explored the effectiveness of immunotherapy in the elderly population. Here, we performed a retrospective analysis to determine the prognostic role of sarcopenia in older patients with SqCLC receiving ICIs. We retrospectively assessed SqCLC patients who were treated with PD-1 inhibitors and all patients were at least 70 years old. Pre-treatment sarcopenic status was determined by analyzing L3 skeletal muscle index (SMI) with chest CT. Progression-free survival (PFS), disease-specific survival (DSS) and overall survival (OS) were estimated using the Kaplan-Meier method, and the differences in survival were compared using the log-rank test. Among 130 male SqCLC patients, 93 had sarcopenia. Patients with sarcopenia were older and had a lower body mass index (BMI). Over an average follow-up of 20.8 months, 92 patients died. For all 130 patients, the mean OS was 13.3 months. Patients with sarcopenia had a significantly shorter OS and PFS than those without sarcopenia (OS, 12.4 ± 5.2 months vs. 15.5 ± 10.5 months, P = 0.028; PFS, 6.4 ± 2.9 months vs. 7.7 ± 4.2 months; P = 0.035). Multivariable analysis showed that sarcopenia was an independent prognostic factor for shorter OS and PFS. CT-determined sarcopenia is an independent prognostic factor for older patients with SqCLC receiving ICIs.

Keywords: Prognosis; Programmed death-1 inhibitors; Sarcopenia; Squamous cell lung cancer

DOI: https://doi.org/10.1038/s41598-024-62825-2

IET Syst Biol. 2024 May 30.

Gene signatures of endoplasmic reticulum stress and mitophagy for prognostic risk prediction in lung adenocarcinoma.

Xiong Lin, Miaoling Yang, Yuanling Huang, Xiaoli Huang, Huibo Shi, Binbin Chen, Jianle Kang, Sunkui Ke.

Genes associated with endoplasmic reticulum stress (ERS) and mitophagy can be conducive to predicting solid tumour prognosis. The authors aimed to develop a prognosis prediction model for these genes in lung adenocarcinoma (LUAD). Relevant gene expression and clinical information were collected from public databases including Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA). A total of 265 differentially expressed genes was finally selected (71 up-regulated and 194 downregulated) in the LUAD dataset. Among these, 15 candidate ERS and mitophagy genes (ATG12, CSNK2A1, MAP1LC3A, MAP1LC3B, MFN2, PGAM5, PINK1, RPS27A, SQSTM1, SRC, UBA52, UBB, UBC, ULK1, and VDAC1) might be critical to LUAD based on the expression analysis after crossing with the ERS and mitochondrial autophagy genes. The prediction model demonstrated the ability to effectively predict the 5-, 3-, and 1-year prognoses of LUAD patients in both GEO and TCGA databases. Moreover, high VDAC1 expression was associated with poor overall survival in LUAD (p < 0.001), suggesting it might be a critical gene for LUAD prognosis prediction. Overall, the prognosis model based on ERS and mitophagy genes in LUAD can be useful for evaluating the prognosis of patients with LUAD, and VDAC1 may serve as a promising biomarker for LUAD prognosis.

Keywords: bioinformatics; genomics; lung; tumours

DOI: https://doi.org/10.1049/syb2.12092