Role of microbiome in cancer and inflammation

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

We use mice deficient for immune or inflammation-related genes, we have established methods for the determination of mouse and human microbiome and we have established a Microbiome core for providing these technologies as a service to the NIH community. We continue to work with germ free mice, gnotobiotic mice with defined intestinal flora, and mice reconstitute after antibiotic treatment. Change within the intratumoral microbiome is a common feature in lung and other cancers and may influence inflammation and immunity in the tumor microenvironment, affecting growth and metastases. We previously characterized the lung cancer microbiome in patients and identified Acidovorax temperans as enriched in tumors. Recently, we instilled A. temperans in an animal model driven by mutant K-ras and Tp53. This revealed A. temperans accelerates tumor development and burden through infiltration of proinflammatory cells. Neutrophils exposed to A. temperans displayed a mature, pro-tumorigenic phenotype with increased cytokine signaling, with a global shift away from IL-1b signaling. Neutrophil to monocyte and macrophage signaling upregulated MHC II to activate CD4+ T cells, polarizing them to an IL-17A+ phenotype detectable in CD4+ and gd populations (T17). These T17 cells shared a common gene expression program predictive of poor survival in human LUAD. These data indicate bacterial exposure promotes tumor growth by modulating inflammation. We were among the very first to show that Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment (Science 342:967-970). We showed that microbiota perturbation impairs the response of subcutaneous cancers to CpG-oligonucleotide-immunotherapy or platinum chemotherapy. Many laboratories have extended our results to cancer immunotherapy in patients and suggested that the microbiome composition determine the ability of patients with melanoma and other type of cancer to respond to anti-PD1 therapy. However, the different studies have identified different types of bacteria has been responsible for this effect and the mechanisms remain unclear. Collectively, our findings show that fecal microbiota transfer (FMT) and anti-PD-1 changed the gut microbiome and reprogrammed the tumor microenvironment to overcome resistance to anti-PD-1 in a subset of PD-1 advanced melanoma. We found that higher dietary fiber was associated with significantly improved progression-free survival in 128 patients on ICB, with the most pronounced benefit observed in patients with sufficient dietary fiber intake and no probiotic use. Findings were recapitulated in preclinical models, which demonstrated impaired treatment response to anti-programmed cell death 1 (anti-PD-1)-based therapy in mice receiving a low-fiber diet or probiotics, with a lower frequency of interferon-g-positive cytotoxic T cells in the tumor microenvironment. Together, these data have clinical implications for cancer patients receiving ICB. Transkingdom Network Analysis (TkNA): a systems framework for inferring causal factors underlying host-microbiota and other multi-omic interactions: we established Transkingdom Network Analysis (TkNA), a unique causal-inference analytical framework that offers a holistic view of biological systems by integrating data from multiple cohorts and diverse omics types. TkNA helps to decipher key players and mechanisms governing host-microbiota (or any multi-omic data) interactions in specific conditions or diseases. TkNA reconstructs a network that represents a statistical model capturing the complex relationships between different omics in the biological system. It identifies robust and reproducible patterns of fold change direction and correlation sign across several cohorts to select differential features and their per-group correlations. The framework then uses causality-sensitive metrics, statistical thresholds and topological criteria to determine the final edges forming the transkingdom network. With the subsequent network's topological features, TkNA identifies nodes controlling a given subnetwork or governing communication between kingdoms and/or subnetworks. Unlike most other multi-omics approaches that find only associations, TkNA focuses on establishing causality while accounting for the complex structure of multi-omic data. Role of gut microbiome in the control of clinical response to Neoadjuvant Vidutolimod and Nivolumab in High-Risk Resectable Melanoma patients: Intratumoral TLR9 agonists and anti-PD-1 therapies provide durable clinical responses and broad immune activation. To evaluate the efficacy and mechanisms of action of this therapeutic combination, we analyzed a single-arm phase 2 neoadjuvant study of TLR9 agonist vidutolimod combined with anti-PD-1 nivolumab in patients with high-risk resectable melanoma. In 31 evaluable patients, 55% (17/31) had major pathologic response (MPR), with eight grade-3 treatment-related adverse events. MPR was associated with necrosis and melanophagocytosis, increased CD8+ tumor-infiltrating lymphocytes and plasmacytoid dendritic cells (pDCs) in the tumor microenvironment, and increased frequencies of Ki67+ CD8+ and CD4+ T cells, pDCs, and monocytes peripherally . Patients with MPR had an enriched gene signature associated with myeloid cells pre-treatment, and response to therapy was associated with gene signatures of immune cells, pDCs, phagocytosis, and macrophage activation. Gut microbiome composition plays a critical role in regulating antitumor immune responses to ICIs in multiple cancers including melanoma. Taxa identified in patients who derived durable benefit from anti-PD-1 monotherapy include several species of the Gram-positive Firmicutes and Actinobacteria phyla, while Gram-negative Proteobacteria and Bacteroidetes are usually associated with poor treatment response. The favorable association of MPR to neoadjuvant vidu/nivo with Gram-negative bacteria, primarily members of the Enterobacteriaceae and Oscillobacteriaceae families, and the negative association with Gram-positive species of the Lachnospiraceae family suggest that the composition of microbiota associated with this combination is almost antithetical to that associated with favorable outcome in melanoma patients treated with anti-PD-1. Our clinical results are remarkably similar to what we previously observed in preclinical models of intratumoral treatment with type B CpG-ODN. In recent years, evidence has shown that the gut microbiome significantly influences responses to immunotherapy. This has sparked interest in targeting it to improve therapy outcomes and predictions of response and toxicity. Research has demonstrated that dysbiosis, often resulting from antibiotic use, can diminish the effectiveness of immune checkpoint inhibitors, and this lack of efficacy could be linked to systemic inflammation. Certain bacterial species have been identified as having beneficial and harmful effects on immunotherapy in the clinic. While a clear consensus has yet to emerge on the optimal species for therapeutic use, introducing a new microbiome into immunotherapy-­refractory patients may boost their chances of responding to further treatment attempts. State-­of-­the-­art interventions targeting the microbiome-such as fecal microbiota transplantation- are being assessed clinically for their safety and potential to enhance treatment outcomes, with promising results. Additionally, the microbiome has been leveraged for its power to predict clinical outcomes using machine learning, and surprisingly, its predictive capability is comparable to that of other described multi-­biomarker clinical scores. We have discussed developing knowledge concerning the microbiome's significance in cancer immunotherapy and outline future strategies for maximizing its potential in immuno-­oncology.