American Association for Cancer Research
23266066cir170582-sup-190733_2_supp_4662842_p6jgh3.pdf (3.62 MB)

Supplementary Figures and Legends from Secretory IgM Exacerbates Tumor Progression by Inducing Accumulations of MDSCs in Mice

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journal contribution
posted on 2023-04-03, 23:20 authored by Chih-Hang Anthony Tang, Shiun Chang, Ayumi Hashimoto, Yi-Ju Chen, Chang Won Kang, Anthony R. Mato, Juan R. Del Valle, Dmitry I. Gabrilovich, Chih-Chi Andrew Hu

S1. Crosslinking and preparation of oligomeric HEL. S2. Oligomeric HEL crosslinks the BCR, and induces robust BCR signal transduction in MD4+/-/Eμ-TCL1+/+ B cells. S3. Oligomeric HEL activates a more rapid BCR signaling than F(ab')2 in MD4+/- and MD4+/-/Eμ-TCL1+/+ B cells. S4. CD11b+/Ly6G+ granulocytic cells or CD11b+/Ly6C+ monocytic cells do not accumulate in the blood and spleens of 6-month-old WT, MD4+/- and μS-/- mice. S5. B cells and CLL cells from MD4+/-/Eμ-TCL1+/+ and Eμ-TCL1+/+ but not μS-/-/E�-TCL1+/+ mice produce sIgM; human CLL cells also produce and secrete IgM. S6. Decreased percentages of CD11b+/Ly6G+ granulocytic cells in spleens of 6-week-old μS-/-/E�-TCL1+/+ mice; decreased percentages of CD11b+/Ly6G+ granulocytic cells and CD11b+/Ly6C+ monocytic cells in the bone marrow of 6-month-old μS-/-/Eμ-TCL1+/+ mice; increased percentages of CD11b+/Ly6G+ granulocytic cells and CD11b+/Ly6C+ monocytic cells in the bone marrow of 6-week-old MD4+/-/Eμ-TCL1+/+ mice; and increased percentages of CD11b+/Ly6G+ granulocytic cells in the bone marrow of 6-month-old MD4+/-/Eμ-TCL1+/+ mice. S7. CD11b+/Ly6G+ granulocytic cells can be purified from the spleens and peripheral blood of MD4+/-/Eμ�-TCL1+/+ mice. S8. CD11b+/Ly6G+ granulocytic cells purified from the spleens or bone marrow of LLC-grafted WT and μS-/- mice have small or little effect in suppressing T cell proliferation.






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. Cancer Immunol Res; 6(6); 696–710. ©2018 AACR.