(782) Natural Antibody Recognition of DAMPs Is Required for Inflammasome-Driven Anti-Tumor Immunity

Introduction/Rationale: Damage-associated molecular patterns (DAMPs) released from malignant cells are known to induce immune responses. Natural Antibodies (Nabs), primarily produced by B1 B cells are known to bind DAMPs and clear out excessive DAMPs associated with cell death, preventing autoimmunity. However, the mechanisms linking NAb mediated DAMP recognition to anti-tumor immunity remain unclear.

Methods: The role of natural antibodies (NAbs) in DAMP-mediated immunity was investigated using transgenic mice deficient in B cells (CD19creDTA) and NAbs (IgHEL MD4). DAMPs including Uric acid, Calreticulin, and HMGB1 were tested for their ability to elicit immune responses against neoantigen-expressing cells. Additional knockout mouse models were used to define signaling pathways triggered by DAMP-NeoAg-NAb complex that promote cytotoxic T lymphocyte (CTL) activation.

Results: In the absence of NAbs, DAMPs failed to induce cytolytic activity or generate neoantigen-specific CTLs, indicating that the circulating NAb repertoire alerts the immune system to the presence of transformed cells. Moreover, B16F10 melanoma models confirmed that NAbs were required to license DAMP-mediated anti-tumor immunity; without them, a significantly greater tumor burden was observed. However, immunization with DAMPs and B16 peptides and restoration of the NAb repertoire resulted in reduced tumor burden.

Conclusion: Natural antibodies are essential for DAMP-induced type 1 immunity, enabling early recognition and elimination of transformed or precancerous cells.