To explore the role of B cell receptor (BCR) in promoting malignant progression of chronic lymphocytic leukemia (CLL) in mice, we generate MD4/Eμ-TCL1 mice, whose B cells harbor a monoclonal BCR against hen egg lysozyme (HEL) and secrete IgM against HEL. MD4/Eμ-TCL1 mice survive significantly shorter than Eμ-TCL1 mice. While precancerous B cells in young MD4/Eμ-TCL1 mice recognize HEL, CLL cells developed in older MD4/Eμ-TCL1 mice fail to recognize HEL. Nevertheless, MD4/Eμ-TCL1 CLL cells can be activated by goat F(ab')2 anti-mouse IgM and respond by phosphorylation of Igα, Syk and ERK1/2, indicating reactivation of a parental Ig gene allele. MD4/Eμ-TCL1 CLL cells also produce large quantities of secretory IgM (sIgM), which does not react with HEL. Compared with age-matched Eμ-TCL1 mice, MD4/Eμ-TCL1 mice also generate a significantly increased population of CD11b+/Ly6G+ granulocytic cells in the peripheral blood, spleens and bone marrow. CD11b+/Ly6G+ granulocytic cells purified from spleens of MD4/Eμ-TCL1 mice can suppress CD3/CD28-mediated proliferation of CD8+ T cells and gp100-loaded class I MHC-mediated proliferation of CD8+ T cells from PMEL-1 mice, qualifying these cells as myeloid-derived suppressor cells (MDSCs). Increased MDSCs may account for significantly decreased T cells and poor prognosis in CLL-bearing MD4/Eμ-TCL1 mice. Because MD4/Eμ-TCL1 mouse CLL cells and human CLL cells can produce sIgM, we hypothesize that sIgM may account for the accumulation of MDSCs. To test this hypothesis, we cross μS-/- mice, which cannot produce sIgM, with Eμ-TCL1 mice. The μS-/-/Eμ-TCL1 mice indeed develop significantly lower numbers of MDSCs, and survive significantly longer than Eμ-TCL1 mice. We decide to target the synthesis of sIgM by deleting the function of XBP-1, because the synthesis of sIgM is tightly regulated by a mechanism called regulated IRE-1-dependent decay (RIDD), which is hyperactivated in B cells as a response to XBP-1 deficiency. We cross B cell-specific XBP-1KO mice with MD4/Eμ-TCL1 mice, and the resultant XBP-1KO/MD4/Eμ-TCL1 mice indeed produce significantly reduced amounts of sIgM and decreased numbers of MDSCs. In addition, μS-/- mice grafted with Lewis lung carcinoma exhibit reduced functions of MDSCs in suppressing T cells, resulting in significantly slower tumor growth. These results clearly demonstrate that sIgM produced by B cells can upregulate the immunosuppressive functions of MDSCs in tumor-bearing mice to aggravate cancer progression.
Citation Format: Chih-Hang Tang, Shiun Chang, Ayumi Hashimoto, Yi-Ju Chen, Chang Won Kang, Anthony Mato, Juan Del Valle, Dmitry Gabrilovich, Chih-Chi Andrew Hu. Secretory IgM exacerbates tumor progression by inducing accumulations of myeloid-derived suppressor cells in mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4756.