A Uniform Computational Approach Improved on Existing Pipelines to Reveal Microbiome Biomarkers of Nonresponse to Immune Checkpoint Inhibitors

Abstract

Purpose: While immune checkpoint inhibitors (ICI) have revolutionized the treatment of cancer by producing durable antitumor responses, only 10%–30% of treated patients respond and the ability to predict clinical benefit remains elusive. Several studies, small in size and using variable analytic methods, suggest the gut microbiome may be a novel, modifiable biomarker for tumor response rates, but the specific bacteria or bacterial communities putatively impacting ICI responses have been inconsistent across the studied populations. Experimental Design: We have reanalyzed the available raw 16S rRNA amplicon and metagenomic sequencing data across five recently published ICI studies (n = 303 unique patients) using a uniform computational approach. Results: Herein, we identify novel bacterial signals associated with clinical responders (R) or nonresponders (NR) and develop an integrated microbiome prediction index. Unexpectedly, the NR-associated integrated index shows the strongest and most consistent signal using a random effects model and in a sensitivity and specificity analysis (P < 0.01). We subsequently tested the integrated index using validation cohorts across three distinct and diverse cancers (n = 105). Conclusions: Our analysis highlights the development of biomarkers for nonresponse, rather than response, in predicting ICI outcomes and suggests a new approach to identify patients who would benefit from microbiome-based interventions to improve response rates.

Composition of gastrointestinal microbiota in association with treatment response in individuals with metastatic castrate resistant prostate cancer progressing on enzalutamide and initiating treatment with anti-PD-1 (pembrolizumab)

“…Recently, Shaikh et al. combined sequencing data from multiple checkpoint inhibition microbiome studies to develop an “integrated index” describing bacteria associated with response and non-response to checkpoint inhibition [37] . In order to further investigate how our results compare to previous published reports, we ran our data through a modified integrated index, optimizing for differences in bacterial classification between the two data sets ( Supplementary File 2 ).…”

“…Taxonomic classification results were mined for sequences from the 17 bacteria included in integrated index from Shaikh et al. [37] . Due to differences in classification, not all species were represented in our data.…”

Human Microbiome and Its Medical Applications

“…Commensal microbiome composition has been reported to be correlated with the responsiveness of patients to ICIs. Enrichment of Roseburia hominis was associated with a responsive immune response to ICIs, while Veillonella parvula was associated with a non-responsive immune response to ICIs ( Shaikh et al, 2021 ). Prediction based on patient microbiome composition showed a good accuracy on ICIs immune responsiveness.…”

Novel emerging biomarkers to immunotherapy in kidney cancer

“…89 This extends to its interplay with cancer therapies, and several studies have pointed to an association between the gut microbiome and outcomes to ICI therapy in solid tumors, highlighting the significance of microbial diversity but also specific bacterial species in this context. 90,91…”