American research identifies cancer-fighting gut microbiome

April 9, 2019

The American Cancer Society has cited metastatic melanoma as the deadliest form of skin cancer; only half of patients respond to immune checkpoint inhibitors in combination therapy, which may involve autoimmune-related side effects, limited durability of response or complete resistance to therapy. Mounting evidence supports the role of the gut microbiome in effective immune therapy, as antibiotics and select probiotics reduce treatment efficacy, while certain bacterial strains enhance efficacy. Personalised cancer treatments based on potential responses to immune checkpoint inhibitors could therefore immensely help patients.

A recent worldwide collaboration led by researchers at Sanford Burnham Prebys (SBP) medical institute, US, has demonstrated a causal link between the gut microbiome and the immune system’s ability to fight cancer. The study also points to the role of unfolded protein response (UPR) as potential biomarkers for personalised immune therapy with select checkpoint inhibitors. 

Thomas Gajewski, MD, the AbbVie Foundation Professor of Cancer Immunotherapy at the University of Chicago Medicine, US, has credited the study highlights of UPR as an important link between gut microbiota and anti-tumor immunity – thus guiding new and potentially successful therapeutic development.

Senior study author and professor at SBP’s designated Cancer Centre, Ze’ev Ronai, and his team have studied a genetic mouse model without the RING finger protein 5 gene (RNF5)that removes inappropriately folded or damaged proteins which may cause tumours – the RNF5-lacking mice were able to inhibit the growth of melanoma tumors with an intact immune system and gut microbiome.

Advanced bioinformatics techniques allowed the identification of 11 bacterial strains that were enriched in the guts of the RNF5-lacking mice – transferring these strains to wild mice that lack intestinal bacteria induced anti-tumor immune response and slowed tumor growth. Further treating these mice with a cocktail of antibiotics or housing the mice with their wild littermates abolished tumor rejection – indicating the important role of the gut microbiome in anti-tumor immunity. Reduced UPR was then identified in immune and intestinal epithelial cells, sufficient for immune cell activation; reduced UPR signaling was also associated with the altered gut microbiomes in the mice.

Corresponding human treatment of metastatic melanoma patients who received checkpoint inhibitor treatment showed a markedly reduced expression of UPR components, or enhanced responsiveness to cancer treatment.

The scientists plan to determine what the bacteria are producing that slows tumor growth. These products could later define possible prebiotics that may enrich their presence in the gut of melanoma patients. Ronai also believes this research could help more patients benefit from immune therapy by eliminating side effects seen for certain immune checkpoint therapies, such as gut inflammation and antibiotic resistance.


Category: Health alert

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