Dados do Resumo

Título

Immune Profiling of Lung Adenocarcinoma in Never-Smoker Patients.

Introdução

Lung cancer is a major public health concern, with approximately 2.5 million new cases reported globally each year. It remains the leading cause of cancer-related mortality, responsible for about 1.8 million deaths annually. In Brazil, lung cancer ranks as the third most common cancer in men and the fourth in women. Although smoking is the primary risk factor, the incidence of lung cancer among never-smokers is rising, accounting for 10% to 30% of cases, underscoring the need for targeted research and new treatment strategies.

Objetivo

To determine the immune profiles of lung adenocarcinoma in never-smoker patients by analyzing the gene expression of immune-related genes and comparing these profiles with those of smokers, with the aim of identifying specific pathways and molecular characteristics associated with lung cancer in never-smokers.

Métodos

The study was approved by the Ethics Committee of FMB (CAAE: 78956524.2.0000.5411). We conducted gene expression analysis on 12 primary tumor and brain metastasis samples from never-smoker patients and a pool of 5 brain metastasis samples from smoker patients using the Nanostring nCounter panel, which profiles 770 immune-related genes. This approach identified significant differences in immune gene expression. Additional RNA-Seq data from 200 lung adenocarcinoma samples were analyzed using CIBERSORT to quantify immune cell fractions, including 22 types of immune cells, validated with two independent GEO datasets, and predictive analyses were conducted using Orange Data Mining software to identify specific immune profiles and pathways linked to never-smokers.

Resultados

The immune profiling using NanoString technology revealed three main cell types with differential expression in primary tumors and brain metastasis from never-smokers: NK CD56dim cells, Treg cells, and exhausted CD8+ cells. Moreover, twelve biological components were identified, based on the differentially expressed genes: adhesion, complement system, cell cycle, cellular function, chemokines, cytokines, interleukins, leukocytes, regulation, Toll-like receptors (TLR), tumor necrosis factor (TNF), and transport. Notably, 20 genes were consistently upregulated in tumors from never smokers, and associated with at least two of these biological components. CIBERSORT analysis identified 10 immune cell populations with differential expression between tumors from never-smokers and smokers, including B cells, CD8+ T cells, CD4+ T cells, macrophages, resting and activated myeloid dendritic cells, activated mast cells, and monocytes. The findings were validated with GEO datasets, showing an accuracy of 81.6% and 66.7% for correctly identifying never-smoker and smoker patients, respectively. ROC analysis showed an AUC of 0.86, indicating high specificity in distinguishing immune profiles between the two groups.

Conclusões

Our results underscore significant differences in the immune profiles of lung adenocarcinoma in never-smokers compared to smokers, revealing potential biological targets for therapeutic interventions. The high specificity in distinguishing these immune profiles highlights the importance of understanding the unique immune landscapes associated with different risk factors, with the potential to enhance personalized treatment strategies and improve patient outcomes.

Financiador do resumo

This work was supported by the Coordination for the Improvement of Higher Education Personnel - Brazil (CAPES) - Funding Code 001.

Palavras Chave

Lung adenocarcinoma; Immune profile; Non-smoking patients