Is Gut Microbiome A Predictive Marker to Response to Immune Checkpoint Inhibitors?

Abstract

Immune checkpoint inhibitors (ICI) are changing the treatment of solid and hematologic malignancies and becoming an integral part of the management of cancer patients. Ipilimumab, a CTLA-4 inhibitor, was associated with significant survival benefit in metastatic melanoma [1]. In addition, PD-1 and PD-L1 inhibitors such as nivolumab, pembrolizumab and atezolizumab showed remarkable clinical responses in multiple cancer types ranging from 20 to 30% when used in monotherapy. These agents are approved by the US FDA in the management of various tumor types such as metastatic melanoma, non-small-cell lung cancer (NSCLC), renal cell carcinoma, classical Hodgkin's lymphoma, urothelial bladder carcinoma and squamous cell carcinoma of the head and neck [2]. Identifying reliable biomarkers for efficacy would be of interest to improve the outcome and overcome resistance.Several candidate biomarkers had been explored including immunological ones such as intratumoral lymphoid infiltrates and intratumoral PD-L1 expression, genetic biomarkers like oncogenic mutations, mutational load and DNA-mismatch repair deficiency [3]. Recently, emerging data show that gut microbiome might affect the efficacy of ICI making it a potential biomarker of response. In addition, the manipulation of the microbiome by broad-spectrum antibiotics leads to increased susceptibility to infections, accumulation of antibiotic resistances, deregulated metabolism and compromised immune homeostasis [4].Recent reports focused on the role of microbiome in the response to ICI. It was first evaluated in murine models and preclinical studies showed the contribution of gut microbiome in the efficacy of ICI. Vetizou et al. demonstrated that tumor progression of sarcomas in mice housed in specific pathogen-free condition was inhibited with anti-CTLA-4 in contrast to mice housed in germ-free (GF) condition [5]. In addition, the use of broadspectrum antibiotics such as colistin and imipenem to eliminate gut microbiata altered the antitumor effect of CTLA-4 inhibitors. It was also confirmed in melanoma and colon cancer models. Moreover, the activation of splenic lymphocytes and tumor-infiltrating lymphocytes mediated by anti-CTLA-4 was significantly decreased in GF and antibiotic-treated mice [5]. When researchers recolonized GF mice and antibiotic-treated mice with bacterial species they found that anti-CTLA-4 anticancer responses could be restored with Bacteroides fragilis, Bacteroides thetaiotaomicron, Burkholderia cepacia, or the combination of B. fragilis and B. cepacia via stimulation of Th1 immune response [6].In a prospective study, 26 patients treated with ipilimumab for metastatic melanoma were enrolled. The authors found that anticancer response was associated with colonization by Firmicutes and specifically by Faecalibacterium prausnitzii L2-6, butyrate producing bacterium L2-21 and Gemmiger formicilis ATCC 27749. Patients having microbiota enriched with Faecalibacterium genus and other Firmicutes had significantly higher progression-free survival (PFS) (p ...