Targeting microbial triggers of gammopathy for immunoprevention

Multiple myeloma (MM) is an incurable plasma cell tumor preceded by a defined preneoplastic state termed as monoclonal gammopathy of undetermined significance (MGUS). Strategies to effectively intercept/prevent clinical malignancy remain an unmet need and are the focus of this application. Changes in microbial communities have been extensively studied in the context of cancer outcomes and therapy. However, very few causal relationships between specific microbes and human malignancies have been defined, and suitable models to study these interactions are lacking. It is increasingly appreciated that MM/MGUS originate in the setting of prior chronic inflammation and B cell activation, but the underlying triggers remain unknown. This application involves three PIs (Dhodapkar, Flavell, Palm) with complementary expertise and a track record of productive collaboration. The application is based on exciting preliminary data describing the discovery of a commensal microbial species that directly engage several human MM-associated B-cell receptors. This is supported by data from new humanized models to study interactions between the human immune system and microbial communities in vivo. The proposal also utilizes biospecimens from MGUS patients treated with a short course of antibiotics to reduce pathogenic bacteria. Studies proposed in this application will characterize the full spectrum of human gut microbes that can potentially serve as antigenic triggers for human B cells and MGUS. It will also evaluate causal relationships between specific microbes and activation of human B cells as well as MGUS cells utilizing newly developed models. Finally, it will evaluate how microbial manipulation in MGUS patients can impact the inflammatory microenvironment known to be present and implicated in the pathogenesis of MGUS and its transition to clinical malignancy. Together, these studies may lead to novel approaches for immune-prevention of clinical MM by targeting the underlying precursor states such as MGUS. Insights from these studies may also have implications for interactions between specific microbes and human B cells, broadly impacting human autoimmunity and cancer immunotherapy.