A novel cancer immunotherapy using tumor-infiltrating B cells in the APCmin/+ mouse model

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.

Emerging roles for IL-25 and IL-33 in colorectal cancer tumorigenesis

“…Cohousing IL-33-deficient and IL-33-replete mice before DSS treatment allowed equilibration of the gut microbiota and abrogated the increased colitis in IL-33-deficient mice seen upon DSS treatment. B cells have also been shown to suppress tumorigenesis in Apc min/+ mice similar to in CAC ( 146 ). However, currently there are no studies that assessed the role of B cells downstream IL-25 or IL-33 outside CAC.…”

Heterogeneity of tertiary lymphoid structures in cancer

“…To investigate spontaneous tumorigenesis in the intestine, the APCmin model carrying a mutant allele of the APC locus, similar to the mutation in humans, is frequently used, and the accumulation of immune cells in proximity to adenomas and/or tumors is described (our own observations and ( 226 )). In addition, the (repetitive) i.p.…”