A prospective evaluation of the gut microbiome as a mediator of lymphoma treatment outcome and systemic immunity

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ABSTRACT/SUMMARY Diffuse large B-cell lymphoma (DLBCL), the most common lymphoma, is a significant clinical problem, with only 60% of patients cured. Mechanisms for how DLBCL, an immune cancer, evades host defenses are poorly understood. Growing evidence suggests that the human gut microbiota (GMB) plays important roles in regulating innate and adaptive immunity, and is associated with therapeutic outcome in multiple solid tumor types. Based on this connection, we hypothesize that the GMB influences lymphoma behavior by altering the anti-tumor immune response. Our preliminary data provide compelling evidence that DLBCL patients: a) have distinct GMB compositions in which many commensal families are lost; and b) show chronic activation in central and effector memory T cells. However, the connections between GMB and lymphoma remain poorly understood, limiting the development of targeted therapies. The overall goal of the proposed research is to investigate longitudinally the impact of GMB signatures on clinical response and systemic immunity in DLBCL. Thus, our specific aims are: Aim 1: To investigate in untreated DLBCL the association between the GMB and treatment response using 16S and full metagenomic shotgun sequencing of stool samples from 300 patients pre-treatment, during treatment, and at 12 months, a validated endpoint for clinical outcome; Aim 2: To evaluate the potential bi-directional associations between GMB and DLBCL by tracking concurrent stool and weekly blood samples which we will analyze with novel Bayesian timeseries methods for a subset of 50 DLBCL patients daily during the first 14 days of treatment, and then in follow-up as in Aim 1; Aim 3: To investigate functional relationships between immune activation and microbial diversity, including translocation of microbial products from the gut into the blood and expansion of antigen-specific T cells directed against poor outcome microbes. The scientific premise is supported by extensive pilot data and rigorous application of established methods. The proposed study is highly innovative, as it will be the first large scale longitudinal and prospective investigation of the GMB in lymphoma, using state of the art methodologies such as, full metagenomic shotgun sequencing, AbSeq, and Bayesian time series analysis. This research has the potential to significantly advance lymphoma research by identifying the GMB and systemic immune pathways that impact treatment failure in DLBCL, and it may provide the biologic insights for new personalized therapeutics. We will build on our findings to develop personalized microbial-based therapies, which could range from dietary changes that would favor growth of organisms we demonstrate to be beneficial, to targeted probiotic therapy and/or fecal transplantation to reduce microbes we show are deleterious. Because gut bacteria are modifiable, our findings could lead in the future to the implementation of tailored microbial-based therapies, a new and minimally toxic treatment paradigm for DLBCL patients, a significant unmet medical need.