Tumor-Associated Carbohydrate Antigens as Immunogenic Targets: The Role of B Cells in Anti-Tumor Immunity 4497

Abstract Description Tumor-associated carbohydrate antigens offer promising targets for immunotherapy due to selective tumor expression and absence on normal cells. Thomsen-nouvelle (Tn) antigen—an N-acetylgalactosamine O-linked monosaccharide—is expressed on a significant fraction of adenocarcinomas including colorectal cancers, and correlates with poor prognosis, metastasis, and low survival. Low levels of natural antibodies to TACAs, including Tn, have been identified in healthy humans, but their role in immunosurveillance and protection is poorly understood. We developed a Tn-expressing C57BL/6-derived CMT93 colorectal cancer line by disrupting the Cosmc gene, which encodes a chaperone protein required for T-synthase galactosylation of Tn antigen, and evaluated the role of B cells and their antibodies in regulating tumor growth. The CMT93-Cosmcko cell line grew aggressive tumors in immunocompetent C57BL/6 mice but more rapidly in B cell-deficient mice. Immunofluorescence tissue staining revealed significant IgM and C4 deposition in tumors of immunocompetent but not B cell-deficient mice, and Tn-reactive antibodies were identified in naïve WT mice, suggesting natural antibodies may restrain tumor growth via the classical complement pathway. Tumors also grew more rapidly in strains with deficiencies in natural antibody production, including mice unable to secrete IgM. These results reveal the critical role natural antibodies play in immunosurveillance and restraining growth of Tn+ solid tumors. Funding Sources NCI/5R01CA272724-03; NIAID/2T32AI007401-32 Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)