Metagenomic and Metabolomic Correlates of Immunotherapy Response in Non-Small Cell Lung Cancer

Background The gut microbiome may influence cancer treatment response, perhaps by immune system interactions, but studies are limited among non-small cell lung cancer (NSCLC) patients. We investigated associations of the pre-treatment gut microbiome and serum metabolome/lipidome with immune checkpoint inhibitor (ICI) response among patients with stage III-IV NSCLC. Methods We conducted an observational cohort study with fecal and blood collection among 66 patients with stage III-IV NSCLC undergoing ICI therapy, using an updated definition of clinical benefit. Fecal whole genome sequencing, plasma untargeted metabolomics, and serum lipidomics were conducted using liquid chromatography mass spectrometry. Multivariable logistic regression estimated associations of alpha/beta diversity, microbial abundance, metabolites, and lipids with clinical benefit. Microbial taxa, metabolites, lipids, and significant lipids correlations were examined. Results Microbiome composition (beta diversity) differed between participants with and without clinical benefit ( P  = 0.03). Those with higher relative abundance of Bifidobacterium were less likely (OR per 1-SD = 0.51, 95%CI = 0.25–0.92, P  = 0.04) to have clinical benefit. Those with higher Ruminococcus prevalence were more likely (OR = 7.00, 95%CI = 1.80-34.47, P  = 0.01) to have clinical benefit. Clinical benefit participants had higher serum concentration of 4-Imidazoleacetate (OR = 6.34, 95%CI = 2.36–22.29, P  = 0.001), 6-Bromotryptophan (OR = 3.84, 95%CI = 1.80-10.17, P  = 0.002), and lyso-phosphatidylcholines (OR = 4.52, 95%CI = 1.59–17.19, P  = 0.01) compared to no clinical benefit, though these findings were not statistically significant after multiple corrections. Conclusions This hypothesis-generating study found Ruminococcus was positively, and Bifidobacterium inversely, associated with ICI response among NSCLC patients. The gut microbiome and related metabolites/lipids were found to be associated with ICI clinical benefit among NSCLC patients. Larger, diverse longitudinal studies are needed to clarify the associations of the microbiome and related metabolites with ICI response among NSCLC patients.