Natural Antibody Recognition of DAMPs Is Required for Inflammasome-Driven Anti-Tumor Immunity 2257202

Introduction 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. Funding Source National Institutes of Health (NIH) grants: NIH grants R35 HL155458 (C.V.J.) National Cancer Institute Cancer Center Support Grant 5P30CA023108 (F.W.K.) NIH NIGMS P20GM130454 (F.W.K.) NIH S10 1S10OD030242, (F.W.K.)