Abstract
Accumulating evidence has suggested a correlation of tumor infiltrating B cells (TiBcs) and a good prognosis of cancer diseases. In some cases, TiBcs appear to have experienced antigen stimulation since they have undergone class-switching and somatic hypermutation and formed tertiary lymphoid structures around tumors together with T cells. Assuming TiBcs include those that recognize some tumor antigens, we sought to investigate their possible usefulness for cell-mediated immunotherapies. To expand usually small number of TiBcs in vitro, we modified our B cell culture system: we transduced B cells with ERT2-Bach2 so that they grow unlimitedly provided with tamoxifen, IL-21 and our original feeder cells. Such cells differentiate into plasma cells and produce antibodies upon withdrawal of tamoxifen, and further by addition of a Bach2-inhibitor in vitro. As a preliminary experiment, thus expanded splenic B cells expressing a transgenic antigen receptor/antibody against hen egg lysozyme were intravenously injected into mice pre-implanted with B16 melanoma cells expressing membrane-bound HEL in the skin, which resulted in suppression of the growth of B16 tumors and prolonged survival of the recipient mice. To test the usefulness of TiBcs for the immunotherapy, we next used APCmin/+ mice as a model that spontaneously develop intestinal tumors. We cultured TiBcs separated from the tumors of APCmin/+ mice as above and confirmed that the antibodies they produce recognize the APCmin/+ tumor. Repeated injection of such TiBcs into adult APCmin/+ mice resulted in suppression of intestinal tumor growth and elongation of the survival of the recipient mice. Serum antibody from the TiBc-recipient mice selectively bound to an antigen expressed in the tumor of APCmin/+ mice. These data suggest a possibility of the novel individualized cancer immunotherapy, in which TiBcs from surgically excised tumor tissues are expanded and infused into the donor patients.
Highlights
We demonstrated that infusion of hen egg lysozyme (HEL)-specific induced germinal center B (iGB) cells (Hy10-iGB) inhibited metastatic growth of B16 melanoma cells expressing membrane-bound HEL (B16-membrane-anchored from of hen egg lysozyme (mHEL)) that were transferred i.v. into mice at the same timing and prolonged survival of the mice [13]
To further verify the efficacy of the iGB-cell-mediated cancer therapy in a mouse model, we examined whether infusion of iGB cells suppress the growth of pre-existing tumor
In the mice injected with Hy10 iGB cells, serum IgG1 concentration was apparently increased by day 7 (Fig 1B) as expected with our previous report [13], considering that the cultured Hy10 iGB cells were mostly IgG1+ and must have differentiated into plasma cells in vivo being free of tamoxifen
Summary
TiBc-derived iGB cells inhibit intestinal tumor growth in APCmin/+ mice in vivo The results of these in vitro studies suggested that Abs produced from TiBc-iGB cells may suppress tumor growth in APCmin/+ mice. Immunohistochemistry staining of the tumor tissues revealed that somewhat increased expression of active (cleaved) caspase3 and decreased expression of Ki67 in the tumors of the mice transferred with TiBc-iGB cells, as compared with those with Int. B-iGB cells or PBS alone (Fig 3E).
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