The Role of the Oral and Gut Microbiomes in Impacting Differential Responses to Cancer Therapy

Vancheswaran Gopalakrishnan, The University of Texas School of Public Health

Abstract

There is growing appreciation of the role of the microbiome in cancer, and evidence in pre-clinical models that the gut microbiome may modulate responses to immune checkpoint blockade - though this has not been well-characterized in patients. We analyzed the oral and gut microbiome in melanoma patients on anti-PD-1 therapy (n=112). Patients were classified as either Responders (R) or Non-responders (NR) based on RECIST criteria. 16S rRNA, and whole-genome shotgun sequencing was performed to characterize the diversity, composition and functional capabilities of the microbiome. Immune profiling via a 7-marker IHC panel of CD3, CD8, PD-1, PD-L1, Granzyme B, RORγT and FoxP3, flow cytometry and cytokine analysis were also performed in available tumors and serum samples at baseline. Notable differences were noted in the diversity and composition of the gut microbiome between responders (R) and non-responders (NR), with significantly higher diversity and abundance of Ruminococcaceae in R. Immune profiling demonstrated significantly increased immune infiltrates in baseline tumor samples of R, with a positive correlation between CD8+ T-cell density and abundance of beneficial bacteria enriched in R. Analysis of systemic immune responses via flow cytometry and cytokine assays revealed that patients with a high abundance of Ruminococcaceae in the gut had higher levels of effector CD4+ and CD8+ T cells in the systemic circulation with a preserved cytokine response to anti-PD-1 therapy. Metagenomic studies revealed functional differences in gut bacteria in R including enrichment of anabolic pathways. A systematic review was also conducted to synthesize existing data on the interplay between the microbiome and immune responses in the context of therapy, revealing highly context-specific associations that vary with both type of cancer and choice of therapy. Together these results have far-reaching implications and suggest that modifications to the gut microbiome could potentially enhance therapeutic responses to immune checkpoint blockade.

Subject Area

Epidemiology|Immunology|Oncology

Recommended Citation

Gopalakrishnan, Vancheswaran, "The Role of the Oral and Gut Microbiomes in Impacting Differential Responses to Cancer Therapy" (2017). Texas Medical Center Dissertations (via ProQuest). AAI10615214.
https://digitalcommons.library.tmc.edu/dissertations/AAI10615214

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