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BOTH EFFECTOR AND INHIBITORY IMMUNE MECHANISMS ARE AMPLIFIED IN CASTRATION-RESISTANT PROSTATE CANCER

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abstract
Immune function is modulated by androgen ablation therapy for prostate cancer. Androgen ablation leads to apoptosis of primary prostate tumor and transient potentiation of immune function. However, immune inhibitory mechanisms employed by the tumor eventually prevent prolonged anti-tumor immunity. The long-term effects of androgen ablation on immune function remain poorly understood. In this dissertation, we show that both effector and inhibitory immune mechanisms are amplified by androgen ablation. In chapter II, we showed that CD8+ T cell responses to a model tumor antigen were transiently enhanced after castration in a prostate tumor model. We also observed a parallel amplification of CD4+CD25+FoxP3+ regulatory T cells (Tregs) in the prostate draining lymph nodes and spleens of castrated tumor bearing mice, which was completely abrogated by IL-2 blockade. Our results suggest a paracrine loop where IL-2 produced by the activated effector T cells after castration leads to expansion of Tregs, which then inhibit CD8+ T cell function. In chapter III, we showed that Tregs were actively attracted into the prostate tumor in response to CCL20-CCR6 mediated chemoattractant signaling after castration. Tumor infiltrating neutrophils (TANs) increased dramatically following castration and expressed elevated amount of CCL20 compared with TANs in intact prostate tumors. Neutrophil depletion in castrated tumor bearing mice prevented Treg recruitment to the prostate tumor. Together, our studies identified two immune inhibitory mechanisms from innate and adaptive immunity respectively, which were amplified in castration resistant prostate cancer. We showed that cross-talk between TANs and Tregs regulated CTL effector function in the prostate tumor. Our studies may improve the current understanding of immune modulatory effects of androgen ablation and facilitate development of novel immunotherapies for the treatment of castration resistant prostate cancer.
subject
immunology
immunotherapy
prostate cancer
contributor
Tang, Shuai (author)
Dubey, Purnima (committee chair)
Alexander-Miller, Martha A (committee member)
Parks, John S (committee member)
Sui, Guangchao (committee member)
Willingham, Mark W (committee member)
date
2013-01-09T09:35:12Z (accessioned)
2014-01-09T09:30:11Z (available)
2012 (issued)
degree
Molecular Pathology (discipline)
embargo
2014-01-09 (terms)
identifier
http://hdl.handle.net/10339/37656 (uri)
language
en (iso)
publisher
Wake Forest University
title
BOTH EFFECTOR AND INHIBITORY IMMUNE MECHANISMS ARE AMPLIFIED IN CASTRATION-RESISTANT PROSTATE CANCER
type
Dissertation

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