Preclinical mouse models have shown that the gut microbiome can modulate therapeutic responses to cancer therapies. Yet, this has not been extensively characterized in humans. Two studies now propose that the gut microbiome is an important host factor that determines the response and primary resistance to anti-programmed cell death protein 1 (PD1) immunotherapy in patients with cancer. “the clinical response to PD1 blockade could be predicted by the composition of the gut microbiome” Both groups initially sought to determine whether the clinical response to PD1 blockade could be predicted by the composition of the gut microbiome. To achieve this, faecal samples were collected from patients with either melanoma, non-small-cell lung cancer (NSCLC) or renal cell carcinoma (RCC) before and after commencement of immunotherapy. Metagenomic shotgun sequencing was then used to quantify bacterial species. A common finding was that high diversity of the gut microbiome correlated with prolonged progression-free survival (PFS) following PD1 inhibition.
The papers are by Routy et al and the other by Gopalakrishnan et al. Routy et al note:
Immune checkpoint inhibitors (ICI) targeting the PD-1/PD-L1 axis induce
sustained clinical responses in a sizeable minority of cancer patients.
Here, we show that primary resistance to ICI can be due to abnormal gut
microbiome composition. Antibiotics (ATB) inhibited the clinical benefit
of ICI in patients with advanced cancer. Fecal microbiota
transplantation (FMT) from cancer patients who responded to ICI (but not
from non-responding patients) into germ-free or ATB-treated mice
ameliorated the antitumor effects of PD-1 blockade. Metagenomics of
patient stools at diagnosis revealed correlations between clinical
responses to ICI and the relative abundance of Akkermansia muciniphila. Oral supplementation with A. muciniphila
post-FMT with non-responder feces restored the efficacy of PD-1
blockade in an IL-12-dependent manner, by increasing the recruitment of
CCR9+CXCR3+CD4+ T lymphocytes into tumor beds.
There clearly are a multiplicity of dimensions in using the immune system to combat cancers. It is essential to view this as a systems problem, understanding that we are a bit ignorant of all of its dimensions.
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