Obese patients with non-small cell lung carcinoma and the intratumor microbiome and immune microenvironment.

Abstract

e20675 Background: Data that obesity is the primary driver of alterations of intratumor microbiota (IM) is accumulating. A particularly unique relationship exists between obesity and lung cancer risk/recurrence, termed the ‘obesity paradox’, or an inverse association between body mass index (BMI) and lung cancer. More specifically, a high BMI is an independent predictor of decreasing lung cancer risk, better treatment outcomes, and overall longer survival, unlike the negative effect of obesity observed in other cancers. This relationship has not yet been explored in non-small cell lung carcinoma (NSCLC) patients. Methods: In this study, IM samples were collected from formalin-fixed samples from racially and ethnically diverse patients, including obese and non-obese patients (i) obese (tumor = 20 and tumor adjacent normal = 6), (ii)non-obese (tumor = 23, tumor adjacent normal = 8), (ii) negative controls (n = 4). Extracted DNA underwent 16S sequencing, and microbial α- and β-diversity was calculated and compared by obesity status. Differential abundance was calculated. We assessed the association between IM composition, clinicopathological characteristics, and outcomes. After rigorous filtration, all OTUS measuring more than 192 in counts in negative controls are removed. Statistical tests included ANOVA, PERMANOVA, and the Wilcoxon test. p-value < 0.05 was considered statistically significant. Phyloseq and ANCOM-BC were utilized for bioinformatics analysis. In a subset of patients, we determined the relative presence of CD8+ cytotoxic and CD4+ helper/regulatory T-cells in the tumor microenvironment of obese and non-obese patients (n = 10), by immunohistochemistry. Results: Microbial richness, genus number, and beta-diversity were associated with obesity status ( p = 0.006, p = 0.013, and p< 0.0001, respectively). Microbes from the genus Thermi and Flavobacteria are enriched in non-obese patients, regardless of tumor status. Both these microbes are associated with early-stage NSCLC. T-cell evaluation showed a higher prevalence of CD4+ compared to CD8+ cells in the obese group (p = < 0.0001), whereas the non-obese group had a higher number of CD8+ cells (p = 0.097). A higher ratio of CD4+/CD8+ is associated with a better response to immunotherapy. No consistent associations were seen between the IM and any other available demographic and clinical features, including age, sex, genetic ancestry, tumor histology, stage, and overall survival. EGFR status was also not associated with specific microbiota. Conclusions: These results confirm that obese patients harbor a distinct lung IM in NSCLC, irrespective of histologic grade or histologic subtype, and may benefit from immune-based therapies regardless of clinical or pathologic stage. Further characterization of these findings in large, prospective studies is needed to elucidate their potential clinical applications.