Journal for immunotherapy of cancer · 2026
IgM promotes antitumor immunity to a Tn-expressing solid tumor.
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Nzuki Hope L, Jennings-Gee Jamie E, Trivette Michaela, Mosher Timothy H, Adams-Sims Alexis E, Hegarty Abigail A, Haas Karen M
Аннотация
BACKGROUND: Altered O-glycosylation is a hallmark of many adenocarcinomas and is often characterized by expression of the Tn antigen. However, the role of B cells in protection against Tn-expressing solid tumors remains poorly understood.
METHODS: We generated a colorectal tumor cell line (CMT93) lacking Cosmc, resulting in high Tn expression. Using mice with defined B-cell abnormalities, including deficiencies in B cells, IgM secretion, natural IgM, and B-cell receptor (BCR) repertoire diversity, we investigated the contribution of B cells and secreted antibody to immunity against Tn-expressing colorectal tumors.
RESULTS: Cosmc-deficient tumors grew more rapidly than parental tumors, and IgM deposition was observed within tumors from wild-type mice, suggesting a potential role for antibody in antitumor defense. Tumor-reactive serum IgM, including Tn-reactive IgM, was present in naïve mice. B cell-deficient muMT, VHB1-8 transgenic mice with a restricted BCR repertoire, CD19-/- mice deficient in natural IgM, and μS-/- mice unable to secrete IgM, lacked tumor-reactive IgM and showed increased tumor burdens, suggesting a protective role for secreted tumor-reactive IgM. Lack of tumor-reactive IgM in VHB1-8 transgenic and μS-/- mice was associated with significant alterations in tumor-infiltrating leukocyte composition. Relative to wild-type mice, tumors from VHB1-8 transgenic and μS-/- mice exhibited significantly increased PD-L1hiLy6G+Ly6C-CD11b+ myeloid cells, but reduced B, T, and natural killer cells, along with reduced major histocompatibility complex class II expression on tumor-associated dendritic cells. Moreover, tumor draining lymph nodes from VHB1-8 transgenic and μS-/- mice showed significant reductions in antibody-secreting cells, including IgG+ plasmablasts, which corresponded with decreased IgM and IgG deposition on tumors.
CONCLUSIONS: These findings support a role for B cells and secreted IgM in restraining the growth of Tn-expressing solid tumors and shaping antitumor immunity against tumors with aberrant O-glycosylation.
METHODS: We generated a colorectal tumor cell line (CMT93) lacking Cosmc, resulting in high Tn expression. Using mice with defined B-cell abnormalities, including deficiencies in B cells, IgM secretion, natural IgM, and B-cell receptor (BCR) repertoire diversity, we investigated the contribution of B cells and secreted antibody to immunity against Tn-expressing colorectal tumors.
RESULTS: Cosmc-deficient tumors grew more rapidly than parental tumors, and IgM deposition was observed within tumors from wild-type mice, suggesting a potential role for antibody in antitumor defense. Tumor-reactive serum IgM, including Tn-reactive IgM, was present in naïve mice. B cell-deficient muMT, VHB1-8 transgenic mice with a restricted BCR repertoire, CD19-/- mice deficient in natural IgM, and μS-/- mice unable to secrete IgM, lacked tumor-reactive IgM and showed increased tumor burdens, suggesting a protective role for secreted tumor-reactive IgM. Lack of tumor-reactive IgM in VHB1-8 transgenic and μS-/- mice was associated with significant alterations in tumor-infiltrating leukocyte composition. Relative to wild-type mice, tumors from VHB1-8 transgenic and μS-/- mice exhibited significantly increased PD-L1hiLy6G+Ly6C-CD11b+ myeloid cells, but reduced B, T, and natural killer cells, along with reduced major histocompatibility complex class II expression on tumor-associated dendritic cells. Moreover, tumor draining lymph nodes from VHB1-8 transgenic and μS-/- mice showed significant reductions in antibody-secreting cells, including IgG+ plasmablasts, which corresponded with decreased IgM and IgG deposition on tumors.
CONCLUSIONS: These findings support a role for B cells and secreted IgM in restraining the growth of Tn-expressing solid tumors and shaping antitumor immunity against tumors with aberrant O-glycosylation.