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Regulation of Protective B cell Anti-Tumor Responses

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abstract
The role of B cells in tumor progression is complex and often overlooked. Specifically, little is known about the extent to which the specialized populations of innate-like B-1a and B-1b cells participate in and contribute to the anti-tumor immune response. The totality of work presented in this document demonstrates novel roles for B-1 cells in the anti-tumor response. B-1a cells are important for the innate response against peritoneal carcinomatosis through the production of natural antibody (nAb) that recognizes tumor cells. The protective B-1a cell anti-tumor response is stimulated by pathogen-associated molecular patterns derived from bacteria. The B-1b cell subpopulation plays an important role in the adaptive humoral response against tumors expressing tumor associated carbohydrate antigens (TACAs). B-1b cells specifically contribute to the antibody response to the TACA, Tn. TACAs are normally masked on healthy cells, which make these carbohydrate antigens ideal targets for the anti-tumor immune response. Thus, there is great interest in developing TACA-based vaccines. Unfortunately, this effort has been hindered by a lack of success in clinical trials. This is potentially due to complex immuno-regulatory mechanisms which ultimately serve to inhibit the protective humoral response against TACA-expressing tumors. The immuno-inhibitory molecule PD-1 is expressed by antigen-activated B cells and suppresses B cell expansion and mucin- and Tn-specific antibody production. These antibodies contribute to the anti-tumor response via a complement-dependent mechanism. Immune-regulation of humoral responses to sialylated TACAs is governed by the inhibitory molecule CD22, which is constitutively expressed by B cells. CD22, is a sialic acid-binding, Ig-like, lectin receptor (Siglec), and was found to significantly suppress antigen-specific antibody responses to mucins bearing sialylated TACAs. Inhibition of CD22 binding of sialic acids using monoclonal antibody blockade during immunization significantly increased anti-mucin antibody production and subsequent protection in mouse models of peritoneal carcinomatosis and prostate cancer. Collectively, the work presented here provides a greater understanding of the intricate mechanisms regulating the humoral response to TACAs and the unique role of different B cell subsets in the anti-tumor response. Finally, it highlights potential novel therapeutic strategies to promote B cell anti-tumor immune responses in the treatment of cancer.
subject
B-1 cells
CD22
PD-1
Tumor Associated Carbohydrate Antigens
contributor
Haro, Marcela (author)
Haas, Karen M (committee chair)
Dubey, Purnima (committee member)
Alexander-Miller, Martha (committee member)
Grayson, Jason (committee member)
Ornelles, David (committee member)
date
2017-01-14T09:35:28Z (accessioned)
2016 (issued)
degree
Microbiology & Immunology (discipline)
2021-12-15 (liftdate)
embargo
2021-12-15 (terms)
identifier
http://hdl.handle.net/10339/64191 (uri)
language
en (iso)
publisher
Wake Forest University
title
Regulation of Protective B cell Anti-Tumor Responses
type
Dissertation

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