Microbiota-derived short-chain fatty acids limit the anti-tumor effect of CTLA-4 blockade

Over the last ten years the use of immune checkpoint blocking antibodies has revolutionized cancer therapy. CTLA-4 and PD-1 blocking antibodies are among the most used immunotherapies in patients with metastatic melanoma, but many patients remain non-responsive and relapse is common. Anti-CTLA-4 treatment is only effective in approximately 20% of patients. Recent studies have suggested that gut microbiota composition is associated with the anti-tumor efficacy of anti-CTLA-4 and anti-PD-1 antibodies but the mechanisms underlying this relationship remain unclear.

It is well known that some commensal bacterial groups in the gut produce metabolites that play a pivotal role in the regulation of immune responses. These metabolites include short-chain fatty acids (SCFAs), mainly acetate (C2), propionate (C3) and butyrate (C4). Considering this, Dr. Nathalie Chaput’s group at the Gustave Roussy Cancer-Research Institute in Villejuif, France hypothesized that the anti-cancer efficacy of anti-CTLA-4 blockade might be influenced by systemic microbial SCFAs.
To test this hypothesis butyrate was given to tumor-bearing mice in drinking water. These mice also received i.p. injections of anti-CTLA-4 or its isotype control. Amazingly, in three different tumor models (CT26, MC38, and MCA101) adding butyrate abolished the anti-tumor effect of anti-CTLA-4. Investigating this further, the authors found that butyrate blocked the anti-CTLA-4 induced maturation of dendritic cells which limited the capacity of the dendritic cells to stimulate T cells and thus limited anti-tumor immunity. Transitioning from mice into humans, the group found that melanoma patients with high blood butyrate levels treated with ipilimumab (anti-CTLA-4) had reduced accumulation of memory T cells.

This study demonstrates that microbiota-derived metabolites influence anti-CTLA-4 anti-tumor effects in mouse models and in melanoma patients treated with ipilimumab.

The authors used Bio X Cell’s anti-mouse CTLA-4 antibody (clone 9D9) to block CTLA-4 signaling in vivo.

Read the full article in Nature Communications: https://www.nature.com/articles/s41467-020-16079-x