Fecal short-chain fatty acids may predict PD-1 inhibitor response
medwireNews: High fecal short-chain fatty acid (SCFA) concentrations are associated with longer progression-free survival (PFS) among patients with solid tumors undergoing treatment with PD-1 inhibitors, study findings indicate.
Motoo Nomura (Kyoto University, Japan) and co-investigators say their findings suggest that “fecal short-chain fatty acid concentrations may be a potential biomarker to identify patients with solid tumors who could benefit from treatment with programmed cell death 1 inhibitors.”
The researchers explain that previous studies have suggested that the gut microbiome profile may impact the efficacy of immune checkpoint inhibitors and that SCFAs – major metabolites produced by the gut microbiota – have been confirmed to modulate immune cell response.
To investigate further, Nomura and team measured fecal and plasma SCFA concentrations in 52 patients (median age 67 years, 44% women) with various metastatic or advanced solid tumors who were treated with nivolumab or pembrolizumab between 2016 and 2019.
During a median follow-up of 2.0 years, 28.8% of patients had a complete or partial response to treatment.
The researchers report in JAMA Network Open that these responders had significantly higher concentrations of fecal acetic acid, propionic acid, butyric acid, isobutyric acid, and valeric acid, and of plasma propionic acid and isovaleric acid than nonresponders.
Among these, high concentrations (determined by recursive partitioning analysis) of fecal acetic acid (≥270 µmol/g), propionic acid (≥90 µmol/g), butyric acid (≥40 µmol/g), and valeric acid (≥15 µmol/g) were significantly associated with longer PFS, with hazard ratios (HRs) for disease progression or death of 0.29, 0.08, 0.31, and 0.53, respectively.
A high plasma isovaleric acid level was also associated with significantly longer PFS, at an HR of 0.38.
Nomura and co-investigators assessed diet among the study participants and found that fecal butyric acid and valeric acid concentrations were both significantly and positively associated with mushroom intake, while valeric acid concentration was also positively associated with the intake of green vegetables and cabbage.
In addition, high mushroom intake was significantly associated with longer PFS, but the researchers caution that dietary information was collected in the year preceding immune checkpoint inhibition, not during treatment.
They therefore say: “Further study is needed in order to clarify the association between dietary intake before or after treatment and fecal SCFAs or the efficacy of [immune checkpoint inhibitors].”
Nonetheless, they conclude that their results “suggest that fecal SCFA concentrations are associated with the efficacy of PD-1 [inhibitor] treatment; thus, SCFAs may be the link between the gut microbiota and PD-1 [inhibitor] efficacy.”
They add: “Elucidation of the mechanism of SCFA-associated immune modulation could allow the discovery of novel targets to improve PD-1 [inhibitor] efficacy in patients with cancer.”
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