Fluctuations in gut microbiome composition during immune checkpoint inhibitor therapy

Programmed cell death protein-1 (PD-1)/PD-1 ligand-1 (PD-L1) blockade therapy, alone or in combination with chemotherapy, has shown remarkable promise for treatment of non-small cell lung cancer (NSCLC). However, the majority of NSCLC patients do not derive clinical benefit, and the predictive value of pre-treatment tumor tissue PD-L1 expression is limited. Development of less invasive biomarkers that could identify responders and non-responders in early on-treatment could markedly improve the treatment regimen. Accumulating evidence suggests that baseline gut microbiota profile is associated with response to PD-1/PD-L1 blockade therapy. However, change in the gut microbiome composition during PD-1/PD-L1 blockade therapy and its relation to response remain unclear. Here, we analyzed pre- and on-treatment fecal samples from five NSCLC patients treated with anti-PD-1 immunotherapy, alone or in combination with chemotherapy, and performed 16S rRNA sequencing. Baseline gut microbiome signature was similar between three responders and two non-responders. While the gut microbiome composition remained stable overall during treatment (R2 = 0.145), responders showed a statistically significant increase in microbiome diversity during anti-PD-1 therapy compared to non-responders (p = 0.0274). Within the diverse microbiota, responders showed decreases in the abundance of genera Odoribacter, Gordonibacter, Candidatus stoquefichus, Escherichia-Shigella, and Collinsella, and increase in abundance of Clostridium sensu stricto 1. In contrast, non-responders demonstrated on-treatment increases in genera Prevotella, Porphyromonas, Streptococcus, and Escherichia-Shigella, and decrease in abundance of Akkermansia. This pilot study identified a trend towards increased change in gut microbiome diversity in NSCLC patients responding to anti-PD-1 therapy. Our study provides rationale for further investigation to test the utility of gut microbiota dynamics as a non-invasive biomarker to predict response to PD-1/PD-L1 blockade therapy for a wide variety of malignancies in larger prospective studies.