A novel cancer immunotherapy using tumor-infiltrating B cells in the APCmin/+ mouse model
Open Access
- 19 January 2021
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 16 (1), e0245608
- https://doi.org/10.1371/journal.pone.0245608
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.Funding Information
- Ministry of Education, Culture, Sports, Science and Technology (17H05803, 19H04818)
- Takeda Science Foundation
This publication has 29 references indexed in Scilit:
- Tumor-infiltrating B cellsOncoImmunology, 2012
- CD20+ Tumor-Infiltrating Lymphocytes Have an Atypical CD27− Memory Phenotype and Together with CD8+ T Cells Promote Favorable Prognosis in Ovarian CancerClinical Cancer Research, 2012
- In-vitro derived germinal centre B cells differentially generate memory B or plasma cells in vivoNature Communications, 2011
- Heme regulates B-cell differentiation, antibody class switch, and heme oxygenase-1 expression in B cells as a ligand of Bach2Blood, 2011
- Immune infiltration in human tumors: a prognostic factor that should not be ignoredOncogene, 2009
- A systematic review of humoral immune responses against tumor antigensCancer Immunology, Immunotherapy, 2009
- Imaging of Germinal Center Selection Events During Affinity MaturationScience, 2007
- ApcMin/+ mouse model of colon cancer: Gene expression profiling in tumorsJournal of Cellular Biochemistry, 2004
- ApcMin: A mouse model for intestinal and mammary tumorigenesisEuropean Journal of Cancer, 1995
- Elimination from peripheral lymphoid tissues of self-reactive B lymphocytes recognizing membrane-bound antigensNature, 1991