Inflammation as a Potential Mechanism of Lung Cancer Disparities in African Americans

Lung cancer is the leading cause of cancer-related mortality in the United States. Despite a gradual decline in overall lung cancer cases, there haven’t been similar improvements in the disparities that exist in lung cancer incidence, mortality and survival. African Americans experience a disparately high incidence of lung cancer independent of tobacco and environmental exposures. One potential explanation is that within African Americans, persisting inflammation, known to promote tumor progression, may be overactivated through a variety of ancestral and environmental factors, resulting in a pro-tumorigenic microenvironment consisting of aberrantly polarized myeloid cells. In this study, we hypothesize that the racial disparities observed in lung adenocarcinoma are potentially linked to a higher proportion of pro-tumorigenic inflammatory myeloid cells within the microenvironment that promotes premalignant lesion progression to invasive carcinoma. To conduct the analysis, single-cell RNA sequencing data from tumor and adjacent normal tissues representing pre-invasive lesions were evaluated for two African American patients using the Scanpy workflow. To study the broad impact of inflammation on the tumor microenvironment within the pre-invasive lesions, the tumor-adjacent normal tissue samples were integrated, and the expression of pro-inflammatory genes was evaluated in myeloid cell clusters. The differentially expressed genes specific to tumor-associated macrophages and neutrophils were used as gene signatures. These signatures were used to perform gene set variational analysis in bulk RNA sequencing data from 54 patients, and the scores were evaluated and compared between African American and non-African American samples with different metadata conditions. Significance analysis was performed on the GSVA scores between populations and the p-values were calculated. Finally, power analysis was conducted, which estimated the optimal sample size needed to achieve 80% statistical power for future studies. Results from scRNA-seq revealed pro-tumorigenic macrophage and neutrophil populations marked by IL1B within tumor-adjacent lung parenchyma from African Americans. In addition, the GSVA analysis on bulk RNA-seq showed signal of increased macrophage and neutrophil scores in African Americans versus Whites though these were not significant due to limited sample size. Further analyses in additional samples are warranted to determine whether these populations have a significant association with the increased incidence of lung cancer in African Americans, and to also further associate with environmental factors including air pollution and social deterministic features.