Secretory IgM Exacerbates Tumor Progression by Inducing Accumulations of MDSCs in Mice

• Published in: Cancer immunology research 2018-06, Vol.6 (6), p.696-710
• Main Authors: Tang, Chih-Hang, Chang, Shiun, Hashimoto, Ayumi, Chen, Yi-Ju, Kang, Chang Won, Mato, Anthony R, Del Valle, Juan R, Gabrilovich, Dmitry I, Hu, Chih-Chi
• Format: Article
• Language: English
• Subjects: Animals; B-Lymphocytes - immunology; B-Lymphocytes - metabolism; Biomarkers; Cell Line, Tumor; Disease Models, Animal; Disease Progression; Granulocytes - immunology; Granulocytes - metabolism; Immunoglobulin M - immunology; Immunophenotyping; Lymphocyte Activation - immunology; Mice; Mice, Knockout; Myeloid-Derived Suppressor Cells - immunology; Myeloid-Derived Suppressor Cells - metabolism; Myeloid-Derived Suppressor Cells - pathology; Neoplasms - immunology; Neoplasms - metabolism; Neoplasms - pathology; Receptors, Antigen, B-Cell - metabolism; Signal Transduction; Spleen - immunology; Spleen - metabolism; Spleen - pathology; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; Tumor Microenvironment - immunology
• ISSN: 2326-6066; 2326-6074
• DOI: 10.1158/2326-6066.CIR-17-0582

Chronic lymphocytic leukemia (CLL) cells can secrete immunoglobulin M. However, it is not clear whether secretory IgM (sIgM) plays a role in disease progression. We crossed the Eμ-TCL1 mouse model of CLL, in which the expression of human TCL1 oncogene was driven by the V(H) promoter-Ig(H)-Eμ enhancer, with MD4 mice whose B cells produced B-cell receptor (membrane-bound IgM) and sIgM with specificity for hen egg lysozyme (HEL). CLL cells that developed in these MD4/Eμ-TCL1 mice reactivated a parental Ig gene allele and secreted IgM, and did not recognize HEL. The MD4/Eμ-TCL1 mice had reduced survival, increased myeloid-derived suppressor cells (MDSC), and decreased numbers of T cells. We tested whether sIgM could contribute to the accumulation of MDSCs by crossing μS mice, which could not produce sIgM, with Eμ-TCL1 mice. The μS /Eμ-TCL1 mice survived longer than Eμ-TCL1 mice and developed decreased numbers of MDSCs which were less able to suppress proliferation of T cells. We targeted the synthesis of sIgM by deleting the function of XBP-1s and showed that targeting XBP-1s genetically or pharmacologically could lead to decreased sIgM, accompanied by decreased numbers and reduced functions of MDSCs in MD4/Eμ-TCL1 mice. Additionally, MDSCs from μS mice grafted with Lewis lung carcinoma were inefficient suppressors of T cells, resulting in slower tumor growth. These results demonstrate that sIgM produced by B cells can upregulate the functions of MDSCs in tumor-bearing mice to aggravate cancer progression. In a mouse model of CLL, production of secretory IgM led to more MDSCs, fewer T cells, and shorter survival times for the mice. Thus, secretory IgM may aggravate the progression of this cancer. .