CD47 is a protein expressed on the surface of many cancer cells, and inhibiting this protein can allow the patient's immune system to attack and destroy the tumour. Antibodies targeting CD47 are currently being tested as treatments for a wide variety of cancers in multiple clinical trials. But studies with laboratory mice have so far yielded mixed results: some mice seem to respond to anti-CD47 treatment, while others do not.
A team of researchers led by Yang-Xin Fu, Professor of Pathology at the University of Texas Southwestern Medical Center and Ralph Weichselbaum, co-director of The Ludwig Center for Metastasis Research at the University of Chicago, found that the response to treatment depends on the type of bacteria living in the animals' guts.
The study, published in the Journal of Experimental Medicine (JEM), reveals that tumour-bearing mice that normally respond to anti-CD47 treatment failed to respond if their gut bacteria were killed off by a cocktail of antibiotics.
In contrast, anti-CD47 treatment became effective in mice that are usually non-responsive when these animals were supplemented with Bifidobacteria, a type of bacteria that is often found in the gastrointestinal tract of healthy mice and humans. Bifidobacteria have previously been shown to benefit patients with ulcerative colitis.
Surprisingly, however, the researchers found that Bifidobacteria do not just accumulate in the gut; they also migrate into tumours, where they appear to activate an immune signalling pathway called the stimulation of interferon genes (STING) pathway.
This results in the production of further immune signalling molecules and the activation of immune cells. When combined with anti-CD47 treatment, these activated immune cells can attack and destroy the surrounding tumour.
"Our study demonstrates that a specific member of the gut microbial population enhances the anti-tumour efficacy of anti-CD47 by colonising the tumour," Fu says. "Administration of specific bacterial species or their engineered progenies may be a novel and effective strategy to modulate various anti-tumour immunotherapies."
Further research
The authors note that further research could look to discover whether other bacterial products produced by Bifidobacterium can also facilitate host responses.
"The checkpoint blockade immunotherapies target T cells directly. These bacteria products improve the antigen-presenting capacity of DCs and elicit robust adaptive immune responses.
"Therefore, these bacterial metabolites may also synergise with other T cell–targeted immunotherapies. Our study opens a new avenue for investigation in clinical practice regarding the microbiome inside TME that synergises with immunotherapy and unravels the situation that some patients fail to respond to immunotherapy."
Source: Journal of Experimental Medicine
Shi. Y., et al.
"Intratumoral accumulation of gut microbiota facilitates CD47-based immunotherapy via STING signaling"
https://doi.org/10.1084/jem.20192282