Gut Microbiome/Metabolome Predicts Response to Immune Checkpoint Blockers in Patients with Recurrent Metastatic Head and Neck Squamous Cell Cancer
Moffitt’s oncology fellow Dr. Shahla Bari presented research findings at ASCO on gut microbiome and gut microbial metabolites and how it can be used as a biomarker to modulate response to immune checkpoint therapy in head and neck cancers. Gut microbiome has emerged as an important predictor of response to ICB therapy in various cancers, although gut microbiome/metabolome signatures of ICB response is unknown in relapsed metastatic head and neck squamous cell cancer patients.
This study included two cohorts of patients, - cohort 1 involved newly diagnosed RM HNSCC patients starting first-line ICB, for whom samples were collected before ICB initiation (baseline) and post-treatment at 3, 6, and 12 months. Cohort 2 patients presented durable response (disease control lasting ≥ 6 months), with single sample collected at study entry. Stool and plasma samples were collected from both groups. 16s rRNA sequencing was performed on stool samples while plasma metabolites were quantitated using Q Exactive plus Orbitrap mass spectrometer. Response was defined as partial response (PR) or complete response (CR).
The results presented the 16-S sequence was carried on 31 samples (cohort 1- 16 baseline, 7 post treatment; cohort 2- 8 durable responders). Targeted metabolomics was completed on 92 plasma samples [cohort 1-27 baseline and 50 post-treatment, cohort 2- 15]. Responders had a significantly higher Shannon’s diversity index, lower Fermicutes to Bacteroidetes ratio, and were enriched with genus Bacteroides and Lachnospiracea incerate sedis at baseline and post treatment, compared to non-responders (p < 0.05). At species level, baseline and post treatment microbiome of responders was enriched with Eubacterium oxidoreducens and Bacteroides uniformis. Ruminococcus was preferentially enriched in durable responders. Targeted analysis of plasma metabolites (associated with gut microbial metabolism) showed that responders had a significantly lower baseline adenosine, Inosine and xanthine level as compared to non-responders. Further, Inosine levels decreased with response, while levels increased in non-responders (p < 0.05), suggestive of consumption by re-activated T cells Further, ICB responders had significantly lower Kynurenine to tryptophan ratio compared to non-responders.
In all, this study was the first to evaluate the association of gut microbiome and metabolome on response to first-line ICB, in RM HNSCC patients. Higher diversity and specific gut microbial signatures associated with ICB response were found. Additionally, the research found that inosine and kynurenine/tryptophan pathways, both of which play a crucial role in host as well as gut microbial metabolism were differentially expressed in ICB responders. These findings, if validated in larger cohort, lays groundwork for gut microbiome and importantly microbial metabolite modulation to improve response to ICB in RM HNSCC.
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