Gut Dysbiosis and Fecal Calprotectin Predict Response to Immune Checkpoint Inhibitors in Patients With Hepatocellular Carcinoma

The gut microbiota is a well-known prognostic factor and a modulator of treatment sensitivity in patients with cancers treated with immune checkpoint inhibitors. However, data on hepatocellular carcinoma (HCC) are lacking. This study aimed to evaluate the prognostic role of the gut microbiota and changes produced by immunotherapy on the intestinal environment in patients with cirrhosis and HCC. Eleven patients treated with Tremelimumab and/or Durvalumab were included in the analysis. All study participants underwent gut microbiota profiling, quantification of fecal calprotectin, serum levels of zonulin-1, lipopolysaccharide binding protein (LBP), and programmed death-ligand 1 (PD-L1) at baseline and at each treatment cycle until the third cycle, then every three cycles until treatment discontinuation or last visit. The 6 patients who achieved disease control (DC) showed lower pretreatment fecal calprotectin (median, 12.5; interquartile range [IQR], 5-29 vs. median, 116; IQR, 59-129 mu g/g; P = 0.047) and PD-L1 serum levels (median, 0.08; IQR, 0.07-0.09 vs. median, 1.04; IQR, 0.17-1.95 ng/mL; P = 0.02) than nonresponders. The relative abundance of Akkermansia (log2 fold change [FC], 2.72; adjusted P [Padj] = 0.012) was increased, whereas that of Enterobacteriaceae (log2 FC, -2.34; Padj = 0.04) was reduced in the DC group. During treatment, fecal calprotectin showed a temporal evolution opposite to the Akkermansia to Enterobacteriaceae ratio and gut microbiota alpha diversity, but similar to zonulin-1 and LBP. Bifidobacterium had a stable behavior in patients with a long follow-up, while Akkermansia was more variable. Akkermansia and Bifidobacterium showed similar temporal patterns and causative relationships with Prevotella, Veillonella, Ruminococcus, Roseburia, Lachnospira, Faecalibacterium, and Clostridium. Conclusion: A favorable composition of the gut microbiota and low intestinal inflammation are associated with achieving DC. The intestinal environment changes dynamically during therapy.