Gut Bacteria Improve Antitumor Immune Response and Immune Checkpoint Blockade Efficacy in Mice

Gut bacteria improve anti-melanoma immune response and strengthens the effects of checkpoint-inhibitor anti-melanoma immunotherapy, researchers report in the journal Science.¹

The researchers found that introducing Bifidobacterium into the guts of mice durably boosts the animals’ anti-melanoma immune responses to levels comparable to those seen with anti-programmed death ligand-1 (PD-L1) antibody-mediated immune checkpoint blockade.

Even more encouragingly, combining Bifidobacterium with PD-L1 blockade therapy “nearly abolished tumor outgrowth” in the mice, the researchers found.¹

“Our results clearly demonstrate a significant, although unexpected, role for specific gut bacteria in enhancing the immune system’s response to melanoma and possibly other tumor types,” said senior author Thomas Gajewski, MD, PhD, professor of medicine and pathology at the University of Chicago.² “The field has recently recognized close connections between the gut microbiome and the immune system. This finding provides a novel way to exploit that connection to improve immunotherapy by selectively modulating intestinal bacteria.”

The findings might help explain why checkpoint inhibitor-blocking agents like ipilimumab, pembrolizumab, and nivolumab can provoke significant immune responses against melanoma (and other malignancies like some lung cancers) for some patients, but not other patients.

Dr. Gajewski’s team suspects that the findings can be explained by “augmented dendritic cell function leading to enhanced CD8+ T-cell priming and accumulation in the tumor microenvironment” after dendritic cells encounter Bifidobacterium in the gut.¹

“Bifidobacterium-treated mice displayed significantly improved tumor control in comparison to non-Bifidobacterium treated counterparts, which was accompanied by robust induction of tumor-specific T cells in the periphery and increased accumulation of antigen-specific CD8+ T cells within the tumor,” they explained.¹ “These effects were durable for several weeks. The therapeutic effect of Bifidobacterium feeding was abrogated in CD8-depleted mice, arguing that the mechanism was not direct but rather through host antitumor T cell responses.”

The study stemmed from researchers’ observation that mice purchased from different laboratories had different immune responses to melanoma tumor grafts, but that when animals from the different labs were housed together for a few weeks, the differences in tumor growth rates largely disappeared, Dr. Gajewski reported. 

References:

1. Sivan A, Corrales L, Hubert N, et al. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science. pii: aac4255. [Epub ahead of print]

2. University of Chicago Medicine. Gut bacteria can dramatically amplify cancer immunotherapy: manipulating microbes maximizes tumor immunity in mice. November 5, 2015. Available at: http://news.uchicago.edu/article/2015/11/06/gut-bacteria-can-dramatically-amplify-cancer-immunotherapy.