The gut microbiota modulates responses to anti–PD-1 and chemotherapy combination therapy and related adverse events in patients with advanced solid tumors

Abstract

BackgroundImmune checkpoint inhibitors (ICIs) targeting programmed cell death protein 1 (PD-1) have been widely used in treating different malignancies. Several studies have reported that the gut microbiota modulates the response and adverse events (AEs) to ICIs in melanoma, non–small cell lung cancer (NSCLC), renal cell cancer and hepatocellular carcinoma, but data on other cancer types and ICI combination therapy are limited.MethodsStool samples were collected from patients with cancer who received anti–PD-1 and chemotherapy combination treatment and were analyzed by fecal metagenomic sequencing. The microbiota diversity and composition were compared between the responder (R) and non-responder (NR) groups and the AE vs. the non-AE (NAE) groups. In addition, associated functional genes and metabolic pathways were identified.ResultsAt baseline, the microbiota diversity of the groups was similar, but the genera Parabacteroides, Clostridia bacterium UC5.1_2F7, and Bifidobacterium dentium were enriched in the R group, whereas Bacteroides dorei and 11 species of Nocardia were enriched in the NR group. At 6 weeks, the beta diversity was significantly different between the R and NR groups. Further analysis found that 35 genera, such as Alipes, Parabacteroides, Phascolarctobacterium, Collinsella, Ruminiclostridium, Porphyromonas, and Butyricimonas and several genera of the Fibrobacteraceae family, were frequently distributed in the R group, whereas 17 genera, including Enterococcus, Lachnoclostridium, Hungatella, and Bilophila and several genera of the Pseudonocardiaceae and Beijerinckiaceae families, were more abundant in the NR group. A total of 66 and 52 Kyoto Encyclopedia of Genes and Genomes (KEGG) orthologs (KOs) were significantly enriched in the R and NR groups, respectively. In addition, pathway analysis revealed functional differences in the gut microbacteria in the R group, including the enrichment of anabolic pathways and DNA damage repair (DDR) pathways. Dynamic comparisons of the bacterial composition at baseline, 6 weeks, and 12 weeks showed that the abundance of Weissella significantly increased in the R group at 6 weeks and the abundance of Fusobacterium and Anaerotruncus significantly increased in the NR group at 12 weeks. Linear discriminant analysis effect size analysis indicated that bacteria of Bacteroidetes, especially Bacteroides, were enriched in the NAE group, whereas flora of Firmcutes, such as Faecalibacterium prausnitzii, Bacteroides fragilis, and Ruminococcus lactaris, were enriched in the AE group.ConclusionBeta diversity and differences in the gut microbiota modulated AEs and the response to anti–PD-1 blockade combined with chemotherapy, by regulating related anabolic and DDR pathways. Dynamic changes in the intestinal microbiome may predict the efficacy of PD-1 inhibitor–based therapy.