Does the gut microbiota play a key role in PD-1/PD-L1 blockade therapy?

Transl Lung Cancer Res 2020 | http://dx.doi. org/10.21037/tlcr.2020. 03.31 Immune checkpoint inhibitors (ICIs), including antiprogrammed cell death-1 (PD-1) and anti-PD-ligand-1 (PD-L1) antibodies have revolutionized the treatment of lung cancer. Most advanced lung cancer patients without driver mutations receive ICIs or ICIs combined with chemotherapy as a first line treatment. Although 10–40% of non-small cell lung cancer (NSCLC) patients have durable responses to ICIs, approximately 30–40% of patients show disease progression 6–8 weeks after the start of ICI treatments if they are treated with anti-PD-1/ PD-L1 monotherapies (1,2). To select patients most likely to respond to ICI treatment, predictive biomarkers have been extensively explored. The expression of PD-L1 on tumor cells is the most established biomarker for anti-PD-1 therapy. However, there are unresolved problems regarding the use of PD-L1 expression as a predictive biomarker, including intratumoral heterogenic expression of PDL1, dynamic changes in PD-L1 expression during cancer treatments, and the unresponsiveness of patients even when their tumors express high levels of PD-L1. The gut microbiota plays an important role in gut health to enhance epithelial barrier integrity and protect against pathogens. The interactions between the gut microbiota and the host immune system have been reported (3,4). Recent studies have demonstrated the association between the gut microbiota and the antitumor effects of ICIs. Sivan et al. found the enhancement of spontaneous antitumor immunity and antitumor efficacy of anti-PD-L1 antibodies in mice with a specific species of bacteria, Bifidobacterium in the gut (5). Dendric cell function and the accumulation of CD8 T cells in the tumor microenvironment were increased in mice with Bifidobacterium. Similar correlations between the gut microbiota and antitumor efficacy of PD-1/PD-L1 blockade therapy have been reported in human cancer patients. The fecal samples from NSCLC patients who were enrolled in the CheckMate 078 and the CheckMate 870 trials and received nivolumab were analyzed (6). High microbiota density and the enrichment of Alistipes putredinis, Bifidobacterium longum and Prevotella copri were associated with improved outcomes, whereas the enrichment of Ruminococcus_unclassified was correlated with poor responses to anti-PD-1 antibodies. Routy et al. evaluated 249 patients, including 140 NSCLC patients, and found that 69 patients (28%) were administered antibiotics 2 months before and 1 month after the start of anti-PD-1/ PD-L1 therapy (7). These 69 patients had significantly worse survival than patients who did not receive antibiotics (median overall survival 11.5 versus 20.6 months, P<0.001). The authors further found that the transplantation of fecal microbiota from cancer patients who responded to ICI treatments, but not from nonresponders, into germ-free mice improved tumor control. This relationship between the gut microbiota and the antitumor effects of anti-PD-1/ PD-L1 therapy is supported by other researcher results (8,9). The following possible mechanisms underlying the modulation of antitumor immunity by the gut microbiota Editorial