Prognostic value of immune-related genes and comparative analysis of immune cell infiltration in lung adenocarcinoma: sex differences

Abstract

Background: Lung adenocarcinoma (LUAD) is one of the most important subtypes of lung cancer. Compared with male LUAD patients, female patients have a higher incidence, but better long-term survival rate, with unknown reasons. In this study, we aimed to explore the effect of sex differences on immune cell infiltration in lung tumor microenvironment (TME), and tried to clarify the reasons for the different clinical characteristics of male and female LUAD patients, by conducting a comparative analysis of the TME. Methods: Using ESTIMATE algorithm, we calculated immune and stromal scores of tumor samples downloaded from TCGA database according to immune or stromal components in TME. GO and KEGG enrichment analysis were conducted to reveal biological processes of these intersecting genes of high- and low-score groups. Cox regression analysis and protein–protein interaction (PPI) network analysis were performed to screen immune-related prognostic genes in female (CCR2, LCP2, and PTPRC) and male (BTK and CCR2) patients. Kaplan–Meier survival analysis was used to evaluate prognostic value of these identified genes. Mann–Whitney test was used to compare various indicators of male patients and female patients. The main results were subsequently validated in 420 cases from GSE72094. Results: 304 and 368 intersecting genes were identified in female and male patients, respectively. The immune score ranged from −943.17 to 3229.35 among female patients and from −541.75 to 3441.78 among male patients. The stromal score ranged from −1790.23 to 2097.27 among female patients and from −1786.94 to 1722.70 among male patients. The immune and stromal scores of women were higher than those of men (p < 0.05). CCR2, LCP2 and PTPRC were identified as the most important immune-related prognostic genes in female LUAD patients. BTK and CCR2 were identified as the most important immune-related prognostic genes in male LUAD patients. Female patients had a higher proportion of memory B cells than that of male patients, while the percentage of T cells CD4 naïve and resting NK cells was lower in female patients (p < 0.05). Conclusions: This study comprehensively compared the differences in tumor immune microenvironment between male and female LUAD patients, and identified prognosis-related genes for patients of different sexes.