bims-meluca 2024-09-08 papers

Cancer Immunol Immunother. 2024 Sep 05. 73(11): 214

Characterization of pre- and on-treatment soluble immune mediators and the tumor microenvironment in NSCLC patients receiving PD-1/L1 inhibitor monotherapy.

Daiki Murata, Koichi Azuma, Kenta Murotani, Akihiko Kawahara, Yuuya Nishii, Takaaki Tokito, Tetsuro Sasada, Tomoaki Hoshino.

BACKGROUND: Despite the favorable therapeutic efficacy observed with ICI monotherapy, the majority of non-small cell lung cancer (NSCLC) patients do not respond. Therefore, identifying patients who could optimally benefit from ICI treatment remains a challenge.
METHODS: Among 183 patients with advanced or recurrent NSCLC who received ICI monotherapy, we analyzed 110 patients whose pre- and post-treatment plasma samples were available. Seventy-three soluble immune mediators were measured at ICI initiation and 6 weeks later. To identify useful biomarkers, we analyzed the association of pre-treatment levels and on-treatment changes of soluble immune mediators with survival of patients. The associations of pre-treatment or on-treatment biomarkers with irAE development, PD-L1 expression, CD8+ TIL density, and neutrophil to lymphocyte ratio (NLR) were also analyzed.
RESULTS: Univariate analysis showed that pre-treatment biomarkers included 6 immune mediators, whereas on-treatment biomarkers included 8 immune mediators. Multivariate analysis showed that pre-treatment biomarkers included 4 immune mediators (CCL19, CCL21, CXCL5, CXCL10), whereas on-treatment biomarkers included 5 immune mediators (CCL7, CCL19, CCL23, CCL25, IL-32). IrAE development was associated with on-treatment change in CCL23. PD-L1 expression was associated with the pre-treatment levels of TNFSF13B and the on-treatment change in CCL25. CD8+ TIL density was associated with the pre-treatment CXCL10 level, whereas NLR was correlated with pre-treatment levels of CCL13 and CCL17.
CONCLUSION: We identified several soluble immune mediators as pre-treatment and on-treatment biomarkers of survival in patients with NSCLC treated with ICI monotherapy. Some of these biomarkers were associated with other possible predictors, including irAE development, PD-L1 expression, CD8+ TIL density and NLR. Further large-scale studies are needed to establish biomarkers for patients with NSCLC who received ICI monotherapy.

Keywords: Biomarker; CD8+ TILs; Chemokine; Cytokine; Immune checkpoint inhibitor; NSCLC

DOI: https://doi.org/10.1007/s00262-024-03781-8

Mol Cell Proteomics. 2024 Aug 29. pii: S1535-9476(24)00124-5. [Epub ahead of print] 100834

Identification of a proteomic signature for predicting immunotherapy response in patients with metastatic non-small cell lung cancer.

Patricia Mondelo-Macía, Jorge García-González, Luis León-Mateos, Alicia Abalo, Susana Bravo, María Del Pilar Chantada Vazquez, Laura Muinelo-Romay, Rafael López-López, Roberto Díaz-Peña, Ana B Dávila-Ibáñez.

BACKGROUND: Immunotherapy has improved survival rates in cancer patients, but identifying those who will respond to treatment remains a challenge. Recent advances in proteomic technologies have enabled the identification and quantification of nearly all expressed proteins in a single experiment. Integration of mass spectrometry with other high-throughput technologies has paved the way for comprehensive and systematic analysis of the plasma proteome in cancer, facilitating early diagnosis and personalized treatment. In this context, the objective of our study was to investigate the predictive and prognostic value of plasma proteome analysis using the SWATH-MS (Sequential Window Acquisition of All Theoretical Mass Spectra) strategy in newly diagnosed NSCLC patients who received pembrolizumab therapy.
METHODS: For this purpose, 64 newly diagnosed advanced NSCLC patients treated with pembrolizumab therapy were enrolled and blood samples were collected from all patients before and during therapy. In total 171 blood samples were collected, and plasma samples were analysed employing SWATH-MS strategy. Next, we compared the plasma protein expression of metastatic NSCLC patients prior to receiving pembrolizumab treatment and divided the cohort into two groups in order to identify a proteomic signature that allow us to predict immunotherapy response.
RESULTS: Proteomic analyses by SWATH-MS strategy allow us to identified 324 differentially expressed proteins between responder and non-responder patients. In addition, we developed a predictive model and found a combination of seven proteins, including ATG9A, DCDC2, HPS5, FIL1L, LZTL1, PGTA, and SPTN2, with stronger predictive value than PD-L1 expression alone. Additionally, survival analyses showed that low levels of ATG9A, DCDC2, and HPS5 were associated with longer progression-free survival (PFS) and overall survival (OS), while low levels of SPTN2 were associated with worse OS.
CONCLUSIONS: Our work highlights the potential value of proteomic technologies to detect predictive biomarkers in blood samples of NSCLC patients. These analyses shed light on the correlation between the response to immunotherapy in patients with NSCLC and the set of 7 proteins.

Keywords: NSCLC; circulating proteins; immunotherapy; predictive biomarkers

DOI: https://doi.org/10.1016/j.mcpro.2024.100834

Front Immunol. 2024 ;15 1444007

AXL expression reflects tumor-immune cell dynamics impacting outcome in non-small cell lung cancer patients treated with immune checkpoint inhibitor monotherapy.

Austin Rayford, Fabian Gärtner, Maria P Ramnefjell, James B Lorens, David R Micklem, Marianne Aanerud, Agnete S T Engelsen.

Introduction: AXL receptor expression is proposed to confer immune-checkpoint inhibitor (ICI)-resistance in non-small cell lung cancer (NSCLC) patients. We sought to interrogate AXL expression in conjunction with mutational and tumor-microenvironmental features to uncover predictive mechanisms of resistance in ICI-treated NSCLC patients.
Methods: Tumor samples from 111 NSCLC patients treated with ICI-monotherapy were analyzed by immunohistochemistry for tumor- and immune-AXL expression. Subsets of patients were analyzed by whole-exome sequencing (n = 44) and imaging mass cytometry (n = 14). Results were related to ICI-outcome measurements.
Results: Tumor-cell AXL expression correlated with aggressive phenotypic features including reduced OS in patients treated with ICIs (P = 0.04) after chemotherapy progression, but conversely associated with improved disease control (P = 0.045) in ICI-treated, PD-L1 high first-line patients. AXL+ immune-cell infiltration correlated with total immune-cell infiltration and improved overall outcomes (PFS: P = 0.044, OS: P = 0.054). Tumor-cell AXL-upregulation showed enrichment in mutations associated with PD-L1-upregulation and ICI-response such as MUC4 and ZNF469, as well as adverse mutations including CSMD1 and LRP1B which associated with an immune-suppressed tumor phenotype and poor ICI prognosis particularly within chemotherapy-treated patients. Tumor mutational burden had no effect on ICI-outcomes and was associated with a lack of tumor-infiltrating immune cells. Spatial-immunophenotyping provided evidence that tumor-cell AXL-upregulation and adverse mutations modulate the tumor microenvironment in favor of infiltrating, activated neutrophils over anti-tumor immune-subsets including CD4 and CD8 T-cells.
Conclusion: Tumor-cell AXL-upregulation correlated with distinct oncotypes and microenvironmental immune-profiles that define chemotherapy-induced mechanisms of ICI-resistance, which suggests the combination of AXL inhibitors with current chemoimmunotherapy regimens can benefit NSCLC patients.

Keywords: AXL receptor tyrosine kinase; NSCLC; biomarker; immunotherapy resistance; tumor microenvironment

DOI: https://doi.org/10.3389/fimmu.2024.1444007

Heliyon. 2024 Aug 30. 10(16): e35940

Deciphering the predictive value of senescence-related signature in lung adenocarcinoma: Implications for antitumor immunity and immunotherapy efficacy.

Yufeng Guo, Yang Wang, Jianchun Duan, Rui Wan, Geyun Chang, Xue Zhang, Zixiao Ma, Hua Bai, Jie Wang.

Objective: The senescence process is pivotal in both the onset and advancement of lung adenocarcinoma (LUAD), influencing cell growth, immune evasion, the potential for metastasis, and resistance to treatments. Senescent cells' dual nature, both harmful and advantageous, adds complexity to understanding their expression patterns and clinical relevance in LUAD. In this study, we sought to evaluate the predictive value of the senescence-related signature in survival outcomes and immunotherapy efficacy in patients with LUAD.
Materials and methods: We integrated data from 1449 LUAD cases sourced from different publicly accessible datasets and a clinical cohort of Chinese LUAD patients. The Cox regression analysis employing the least absolute shrinkage and selection operator (LASSO) was performed on 156 senescence-associated genes to develop the senescence-related signature. Kaplan-Meier analysis and time-dependent receiver operating characteristic curves were utilizaed to assess the prognostic significance of the senescence-related signature. Functional annotation, immune infiltration analysis, and gene set variation analysis were applied to investigate the association of the senescence-related signature with anti-tumor immunity in LUAD. Immunotherapy cohorts of non-small cell lung cancer, urothelial carcinoma, skin cutaneous melanoma, and glioblastoma patients were included to assess the senescence-related signature in predicting immunotherapy efficacy.
Results: The senescence-related signature, which encompasses seven senescence-related genes, namely, FOXM1, VDAC1, PPP3CA, MAPK13, PIK3CD, RRAS, and CCND3, was identified to have predictive significance across multiple LUAD cohorts and demonstrated a negative association with antitumor immunity and tumor-infiltrating neutrophils. Patients exhibiting low expression levels of the senescence-related signature responded more favorably to immune checkpoint inhibitors in various solid tumors, including LUAD. Inhibiting FOXM1 pharmacologically with thiostrepton produced tumor-suppressive effects and improved immunotherapy responses in a Lewis lung carcinoma mouse model.
Conclusions: The senescence-related signature demonstrates potential in predicting patient prognosis and immunotherapy efficacy in LUAD.

Keywords: Cellular senescence; FOXM1; Immunotherapy; LUAD; Neutrophils

DOI: https://doi.org/10.1016/j.heliyon.2024.e35940

Aging (Albany NY). 2024 Aug 28. 16

RPL22L1 is a novel biomarker for prognosis and immune infiltration in lung adenocarcinoma, promoting the growth and metastasis of LUAD cells by inhibiting the MDM2/P53 signaling pathway.

Shigui Xing, Dongbing Li, Qi Zhao.

The ribosomal protein L22-like1 (RPL22L1) is a constituent of the 60 S ribosomal subunit whose function in lung adenocarcinoma (LUAD) remains ambiguous. This study aims to elucidate the role of RPL22L1 in LUAD through a thorough analysis and experimental validation. Our findings indicate that RPL22L1 exhibits abnormal expression patterns in various cancer types, including LUAD. Moreover, a statistically significant association was observed between elevated levels of RPL22L1 expression in LUAD patients and several clinical parameters, such as pathological stage (p = 0.0083) and gender (p = 0.0038). The high expression of RPL22L1 in LUAD demonstrated a significant association with poorer overall survival (OS) (p = 0.005), progression-free survival (PFS) (p = 0.027), and disease-specific survival (p = 0.015). The expression of RPL22L1 in LUAD (p = 0.005) was identified as an independent prognostic factor. Additionally, RPL22L1 expression in LUAD was found to be correlated with immune infiltration, immune checkpoint genes, TMB/MSI, and mRNAsi. Notably, the expression of RPL22L1 exhibited significant negative correlations with 1-BET-762, Trametinib, and WZ3105 in LUAD. The RPL22L1 gene exhibited up-regulation in multiple individual cells of LUAD, leading to a comparatively shorter PFS in the RPL22L1 variant group as opposed to the RPL22L1 variant-free group in LUAD. Significantly increased expression of RPL22L1 was noted in LUAD cell lines, where it was found to enhance the growth and metastasis of LUAD cells by suppressing the MDM2/P53 signaling pathway. Therefore, RPL22L1 may serve as a promising prognostic biomarker and therapeutic target for patients with LUAD.

Keywords: MDM2/P53; RPL22L1; biomarker; immune infiltration; lung adenocarcinoma; prognosis

DOI: https://doi.org/10.18632/aging.206096