Scientists at the Wistar Institute have found that soluble antibodies promote tumor progression by inducing accumulation of myeloid-derived suppressor cells (MDSCs) in preclinical cancer models. Their study (“Secretory IgM Exacerbates Tumor Progression by Inducing Accumulations of MDSCs in Mice”) appears in Cancer Immunology Research.
“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 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 (MDSCs), 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,” write the investigators.
“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.”
CLL is a malignancy characterized by the progressive accumulation of mature B cells. Several reports indicated that B cells can mediate immune suppression and negatively affect the antitumor immune response in several cancer types. The Wistar team, led by Chih-Chi Andrew Hu, Ph.D., associate professor in Wistar's Immunology, Microenvironment & Metastasis Program, and colleagues, used CLL and lung cancer mouse models to better define the role of soluble antibodies produced by B cells in orchestrating the immune suppressive response.
“Our research highlights the contribution of soluble antibodies in inducing accumulation of MDSCs,” said Dr. Hu. “These are a population of immune suppressive cells that inhibit the antitumor functions of T cells and cause worse outcomes in many cancer types.”
Through crossing experiments, the researchers generated a mouse model of CLL in which malignant B cells produced abundant amounts of soluble antibodies, whereas CLL cells were considered to produce primarily membrane-bound antigen receptors. As a result, the mice developed significantly increased numbers of a specific cell population in the blood, which the researchers characterized as MDSCs.
To examine the role of soluble antibodies in the accumulation of MDSCs, they included an additional model of CLL in which B cells can only produce membrane-bound antigen receptors but not soluble antibodies. Survival was longer and there was a significantly lower number of MDSCs, which also had lower ability to suppress T cells, thus suggesting that soluble antibodies are responsible for accumulation of immune suppressive MDSCs.
Impairing the synthesis of soluble antibodies in tumor-bearing mice may be useful to slow down tumor progression, according to Dr. Hu. In fact, genetic and pharmacological targeting of the IRE-1/XBP-1 pathway of the endoplasmic reticulum stress response, which is critical for antibody production, results in decreased numbers and reduced functions of MDSCs. Dr. Hu and his collaborator, Juan R. Del Valle, Ph.D., at the University of South Florida are developing novel small-molecule inhibitors against IRE-1 to combat cancers associated with high numbers of MDSCs.
The researchers expanded the relevance of these findings to lung carcinoma, showing that soluble antibodies are generally important in the tumor microenvironment to induce accumulation of MDSCs and promote cancer progression.
“We suggest that soluble antibodies may execute their immune suppressive function by recruiting MDSCs in the tumor microenvironment or promoting their functions,” said Chih-Hang Anthony Tang, M.D., Ph.D., a staff scientist in the Hu lab and the first author of the study. “Another possibility is that soluble antibodies may stimulate other types of immune cells to produce soluble factors that in turn contribute to the expansion of MDSCs and their functions.”