Gut microbiota signatures are associated with toxicity to combined CTLA-4 and PD-1 blockade

Treatment with combined immune checkpoint blockade (CICB) targeting CTLA-4 and PD-1 is associated with clinical benefit across tumor types, but also a high rate of immune-related adverse events. Insights into biomarkers and mechanisms of response and toxicity to CICB are needed. To address this, we profiled the blood, tumor and gut microbiome of 77 patients with advanced melanoma treated with CICB, with a high rate of any >= grade 3 immune-related adverse events (49%) with parallel studies in pre-clinical models. Tumor-associated immune and genomic biomarkers of response to CICB were similar to those identified for ICB monotherapy, and toxicity from CICB was associated with a more diverse peripheral T-cell repertoire. Profiling of gut microbiota demonstrated a significantly higher abundance of Bacteroides intestinalis in patients with toxicity, with upregulation of mucosal IL-1 beta in patient samples of colitis and in pre-clinical models. Together, these data offer potential new therapeutic angles for targeting toxicity to CICB. Clinical benefit or intestinal toxicity resulting from combined immune checkpoint blockade in patients with melanoma associates with prevalent commensal bacteria and can be decoupled by IL-1R inhibition.

Automated summary

The study showed that tumor-associated immune and genomic biomarkers of response to combined immune checkpoint blockade (CICB) in melanoma patients were similar to those of monotherapy, while toxicity from CICB was associated with a more diverse peripheral T-cell repertoire. Additionally, analysis of gut microbiota revealed a higher abundance of Bacteroides intestinalis in patients experiencing toxicity, along with an upregulation of the inflammatory factor IL-1 beta in colitis samples.