Secretory IgM Exacerbates Tumor Progression by Inducing Accumulations of MDSCs in Mice
Document Type
Article
Publication Date
6-2018
Digital Object Identifier (DOI)
https://doi.org/10.1158/2326-6066.CIR-17-0582
Abstract
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.
Was this content written or created while at USF?
Yes
Citation / Publisher Attribution
Cancer Immunology Research, v. 6, issue 6, p. 696-710
Scholar Commons Citation
Tang, Chih-Hang A.; Chang, Shiun; Hashimoto, Ayumi; Chen, Yi-Ju; Kang, Chang Won; Mato, Anthony R.; Del Valle, Juan R.; Gabrilovich, Dmitry I.; and Hu, Chih-Chi A., "Secretory IgM Exacerbates Tumor Progression by Inducing Accumulations of MDSCs in Mice" (2018). Chemistry Faculty Publications. 78.
https://digitalcommons.usf.edu/chm_facpub/78
