Short-Chain Fatty Acids May Predict ICI Response

Author: By Shreeya Nanda, Senior medwireNews Reporter 

medwireNews: Faecal levels of certain short-chain fatty acids (SCFAs) could help identify patients with solid tumours who are most likely to benefit from immune checkpoint inhibitor (ICI) treatment, suggest Japanese researchers. 

They explain that previous studies have revealed a link between the gut microbiome and efficacy of ICIs, but the mechanism underlying this association remains unclear. 

The investigators led by Motoo Nomura, from Kyoto University, add that SCFAs are “major end product metabolites produced by the gut microbiota and have wide-ranging impacts on host physiology”, including modulating immune cell responses. 

They therefore evaluated faecal and plasma SCFAs in 52 patients who received nivolumab or pembrolizumab for advanced or metastatic cancer (most commonly melanoma, at 46%) between July 2016 and February 2019 at Kyoto University Hospital and were followed up for a median of 2 years. 

According to the report published in JAMA Network Open, the faecal concentrations of propionic acid, acetic acid, butyric acid and valeric acid were significantly higher among the 28.8% of patients with an objective response to ICI therapy than among the nonresponders. 

For instance, the median concentration of propionic acid was 172.6 μmol/g in responders versus 103.6 μmol/g in nonresponders, with corresponding levels of 346.4 and 216.7 μmol/g for acetic acid. 

Similarly, plasma levels of propionic acid and isovaleric acid were significantly higher among participants who did versus did not achieve a response. 

And univariate analysis showed a significant association between longer progression-free survival (PFS) and high faecal levels of propionic acid, acetic acid, butyric acid and valeric acid, with hazard ratios (HRs) of 0.08, 0.29, 0.31 and 0.53, respectively. High plasma concentrations of isovaleric acid were also significantly associated with longer PFS, at an HR of 0.38. 

Motoo Nomura and colleagues note, however, that only propionic acid levels remained significantly associated with improved PFS in multivariate analysis (HR=0.07). 

These results suggest that “SCFAs may be the link between the gut microbiota and PD-1 [inhibitor] efficacy”, they write. 

“Because fecal examinations are completely noninvasive, they may be applicable for routine monitoring of patients.” 

But highlighting the limitations of the study, such as “the small sample size, lack of a validation cohort, and the limited number of gut microbial metabolites evaluated”, the team concludes that additional research is needed to confirm these findings. 

Reference 

Nomura M, Nagatomo R, Doi K, et al. Association of short-chain fatty acids in the gut microbiome with clinical response to treatment with nivolumab or pembrolizumab in patients with solid cancer tumors. JAMA Netw Open 2020; 3: e202895. Published online 16 April 2020. doi: 10.1001/jamanetworkopen.2020.2895