Microbial dysbiosis with tryptophan metabolites alteration in lower respiratory tract is associated with clinical responses to anti-PD-1 immunotherapy in advanced non-small cell lung cancer.

Lower respiratory tract microbiome constitutes a unique immune microenvironment for advanced non-small cell lung cancer as one of dominant localized microbial components. However, there exists little knowledge on the associations between this regional microbiome and clinical responses to anti-PD-1 immunotherapy from clinical perspectives. Here, we equivalently collected bronchoalveolar lavage fluids from 56 advanced NSCLC participants treated with none (untreated, n = 28) or anti-PD-1 immunotherapy (treated, n = 28), which was further divided into responder (n = 17) and non-responder (n = 11) subgroups according to clinical responses, aiming to compare their microbial discrepancy by performing metagenomic sequencing and targeted metabolic alterations by tryptophan sequencing. Correspondingly, microbial diversities transformed significantly after receiving immunotherapeutic agents, where Gammaproteobacteria and Campylobacter enriched, but Escherichia, Streptococcus, Chlamydia, and Staphylococcus reduced at the genus level, differences of which failed to be achieved among subgroups with various clinical responses (responder or non-responder; LDA > 2, P < 0.05^*). And the relative abundance of Staphylococcus and Streptomyces was escalated in response subgroup to anti-PD-1 immunotherapy by microbial compositional analysis (as relative abundance ≥ 3%, P < 0.05^*), no significance of which was achieved among treated and untreated groups. In addition, relative abundances of bacterial tryptophan metabolites and its derivatives were also higher in the responder subgroup, distinctively being associated with divergent genera (VIP > 1, P < 0.05^*). Our study revealed predictive performance of lower respiratory tract microbiome to antitumoral immunotherapy and further suggested that anti-PD-1 immunotherapy may alter lower respiratory tract microbiome composition and interact with its tryptophan metabolites to regulate therapeutic efficacy in advanced NSCLC, performing as potential biomarkers to prognosis and interventional strategies.