Wednesday, January 15, 2025
1/15/2025
Abstract: B cell malignancies comprise more than 50% of blood cancers, approximately 85% of lymphomas, and all myelomas. Despite recent treatment advancements that significantly prolong patient survival, many B cell malignancies remain incurable, highlighting the necessity for a deeper understanding of the disease pathogenesis. During the past 3 decades, research efforts on the pathogenesis of B cell malignancies have been primarily focused on the genetic and epigenetic alterations as well as their oncogenic signaling pathways. Recent endeavors have advanced the understanding of the influence of stromal cells and immune cell subsets on malignant B cells in the tumor microenvironment. This new R01 project aims to elucidate novel paradigm- shifting mechanisms of B cell tumorigenesis, treatment resistance, and relapse driven by commensal bacteria- derived molecules. We reason that commensal bacteria outnumber human cells in the body and constitute the largest pool of antigens for B cell antigen receptors (BCRs) and ligands for Toll-like receptors (TLRs) expressed on B cells in humans. Although commensal bacteria have been implicated in the carcinogenesis of other human cancers such as colon, colorectal, pancreatic, liver, lung, and breast cancers, B lymphocytes are the only cell type of the human body that expresses specific antigen receptors (BCRs) and can produce specific antibodies in response to commensal bacterial antigens. Even in the absence of commensal bacteria transmigration or systemic infection, commensal bacterial antigens and ligands, in the format of soluble molecules or large fragments, can be released from commensal bacteria via secretion, shedding, digestion, or bacterial death-associated decomposition. Such commensal bacteria-derived soluble molecules or large fragments, including antigens and ligands, may gain access to various B cell subsets in lymphoid organs through the blood circulation and lymphatic drainage. However, investigation of commensal bacteria-derived molecules in B cell tumorigenesis is lacking. We will address this critical gap in cancer research. Based on our proof-of-concept preliminary data, we will test the central hypothesis that commensal bacterial molecules can engage BCR and TLR signaling to drive B cell tumorigenesis, treatment resistance, and relapse. We will further exploit such new knowledge to develop novel diagnostics and therapeutics to improve early detection and treatment of B cell malignancies and to prevent relapse. Such commensal bacteria-based diagnostics and therapeutics have mechanisms of action distinct from and complementary to currently available diagnostics and therapeutics, and therefore can be easily integrated into the current standard-of-care system to transform the management landscape of B cell malignancies and improve patient outcome.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).