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A novel cancer immunotherapy using tumor-infiltrating B cells in the APC (min/+) mouse model

WANG XINYING 東京理科大学 DOI:info:doi/10.20604/00003624

2021.06.09

概要

Tumor infiltrating lymphocytes (TILs) have been implicated in the good prognosis of patients with several types of cancers. Among the TILs, much attention has been focused on cytotoxic T cells, clinical application of which as so called TIL therapy have achieved a great success in some cancers. Recent reports have also suggested a correlation of tumor infiltrating B cells (TiBcs) and a good prognosis of cancer diseases. In some cases, TiBcs appear to have been antigen-experienced and clonally expanded based on their class-switching and somatic hypermutation patterns and forms tertiary lymphoid structures around tumors together with T cells and dendritic cells. Assuming TiBcs include those that recognize some antigens expressed on tumor cells, we sought to test whether TiBcs from surgically extracted tumor tissues can be utilized for cellmediated immunotherapies. We previously demonstrated that splenic B cells carrying immunoglobulin transgenes encoding an antibody against hen egg lysozyme (HEL), having been expanded by our original culture system, could produce anti-HEL IgG antibodies in vivo and suppress metastatic growth of a mouse melanoma cells expressing HEL on their cell membrane (B16-mHEL), when injected intravenously into normal mice at the same timing as the B16-mHEL cells. In the present study, we modified the B cell culture system: we transduced the B cells with ERT2 -Bach2- so that the cells grow unlimitedly provided with tamoxifen in our culture system and they differentiate into plasma cells and produce antibodies upon withdrawal of tamoxifen and addition of heme, a Bach2-inhibitor. As shown here, thus prepared HEL-specific B cells, after intravenous injection, could inhibit growth of B16-mHEL cells that had been pre-implanted into skin and elongated the survival of recipient mice. This result suggested a potential application of antigen-specific B cells for immunotherapy and prompted us to test a possible application of TiBcs for tumor immunotherapy using APCmin/+ mice as a model of spontaneous intestinal tumors. TiBcs separated from the intestinal tumors of APCmin/+ mice were cultured as above and induced to produce antibodies which could stain the tumor but not normal area in the intestine of APCmin/+ mice. We repeatedly injected thus propagated TiBcs into adult APCmin/+ mice, which suppressed growth of intestinal tumors and elongated the survival of the recipient mice, perhaps through binding to some tumor-specific antigens by antibodies produced by the injected TiBcs. These data indicate a possibility of TiBc-mediated immunotherapy for cancer patients.

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