NEGATIVE MODULATION OF REGULATORY T CELLS AND PROMOTION OF THE TUMORICIDAL ACTIVITY OF DENDRITIC CELLS IN CANCER: A DOUBLE-EDGED STRATEGY

Persistent Link:
http://hdl.handle.net/10150/146077
Title:
NEGATIVE MODULATION OF REGULATORY T CELLS AND PROMOTION OF THE TUMORICIDAL ACTIVITY OF DENDRITIC CELLS IN CANCER: A DOUBLE-EDGED STRATEGY
Author:
LaCasse, Collin James
Issue Date:
2011
Publisher:
The University of Arizona.
Rights:
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
Embargo:
Embargo: Release after 10/22/2011
Abstract:
Cancer is one of the most pervasive health problems in the world today. Despite major advances in its treatment in recent decades, conventional therapies have seen limited success. Aggressive, drug-resistant cancer cells can reemerge after treatment, resulting in relapse. Immunotherapy, a strategy that utilizes a patient's own immune system to specifically destroy cancer cells, is a potential solution to this problem. Immunotherapy, however, is limited by multiple mechanisms of cancer-induced immunosuppression. One of the most important of these mechanisms is the induction of Treg, which are capable of suppressing multiple arms of the anti-cancer immune response. In the current study, we evaluated strategies to hinder the deleterious function of Treg on cancer immunotherapy. First, we determined that imatinib mesylate could inhibit Treg function in vivo and in vitro and increase the efficacy of dendritic cell-based immunization against an imatinib-resistant lymphoma. Then, searching for further methods to inhibit Treg, we found that Th-1 cells were capable of inhibiting Treg function and synergizing with a tumor lysate vaccine to treat leukemia. This process was dependent on IFN-γ secretion by the Th-1 cells. While investigating the influence of Th-1 on Treg and the resulting immunomodulatory effects of these cells in vivo, we discovered that they were capable of promoting the non-conventional direct tumor killing function of DC. We determined that Th-1 induce the cytotoxic function of bone marrow-derived DC generated with GM-CSF and IL-4 by a mechanism dependent on IFN-γ. Finally, because our results indicate that the antigen presenting function of KDC may depend upon their cytotoxic ability, and since DC generated with IL-15 have been reported to be more efficient APC than those generated with IL-4, we evaluated their ability to also function as direct tumor cell killers. We found that while IL-15 DC can indeed kill tumor cells, only LPS and not IFN-γ was capable of inducing this capability. These findings contribute to both arms of anti-cancer immunity by impairing immunosuppression with imatinib and Th-1, and promoting anti-tumor immunity with KDC. This double-pronged approach may contribute to further strategic advances in the field of cancer immunotherapy.
Type:
text; Electronic Dissertation
Keywords:
cancer; dendritic cell; immunology; immunotherapy; regulatory t cell
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Graduate College; Immunobiology
Degree Grantor:
University of Arizona
Advisor:
Larmonier, Nicolas; Katsanis, Emmanuel

Full metadata record

DC FieldValue Language
dc.language.isoenen_US
dc.titleNEGATIVE MODULATION OF REGULATORY T CELLS AND PROMOTION OF THE TUMORICIDAL ACTIVITY OF DENDRITIC CELLS IN CANCER: A DOUBLE-EDGED STRATEGYen_US
dc.creatorLaCasse, Collin Jamesen_US
dc.contributor.authorLaCasse, Collin Jamesen_US
dc.date.issued2011-
dc.publisherThe University of Arizona.en_US
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en_US
dc.description.releaseEmbargo: Release after 10/22/2011en_US
dc.description.abstractCancer is one of the most pervasive health problems in the world today. Despite major advances in its treatment in recent decades, conventional therapies have seen limited success. Aggressive, drug-resistant cancer cells can reemerge after treatment, resulting in relapse. Immunotherapy, a strategy that utilizes a patient's own immune system to specifically destroy cancer cells, is a potential solution to this problem. Immunotherapy, however, is limited by multiple mechanisms of cancer-induced immunosuppression. One of the most important of these mechanisms is the induction of Treg, which are capable of suppressing multiple arms of the anti-cancer immune response. In the current study, we evaluated strategies to hinder the deleterious function of Treg on cancer immunotherapy. First, we determined that imatinib mesylate could inhibit Treg function in vivo and in vitro and increase the efficacy of dendritic cell-based immunization against an imatinib-resistant lymphoma. Then, searching for further methods to inhibit Treg, we found that Th-1 cells were capable of inhibiting Treg function and synergizing with a tumor lysate vaccine to treat leukemia. This process was dependent on IFN-γ secretion by the Th-1 cells. While investigating the influence of Th-1 on Treg and the resulting immunomodulatory effects of these cells in vivo, we discovered that they were capable of promoting the non-conventional direct tumor killing function of DC. We determined that Th-1 induce the cytotoxic function of bone marrow-derived DC generated with GM-CSF and IL-4 by a mechanism dependent on IFN-γ. Finally, because our results indicate that the antigen presenting function of KDC may depend upon their cytotoxic ability, and since DC generated with IL-15 have been reported to be more efficient APC than those generated with IL-4, we evaluated their ability to also function as direct tumor cell killers. We found that while IL-15 DC can indeed kill tumor cells, only LPS and not IFN-γ was capable of inducing this capability. These findings contribute to both arms of anti-cancer immunity by impairing immunosuppression with imatinib and Th-1, and promoting anti-tumor immunity with KDC. This double-pronged approach may contribute to further strategic advances in the field of cancer immunotherapy.en_US
dc.typetexten_US
dc.typeElectronic Dissertationen_US
dc.subjectcanceren_US
dc.subjectdendritic cellen_US
dc.subjectimmunologyen_US
dc.subjectimmunotherapyen_US
dc.subjectregulatory t cellen_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.disciplineImmunobiologyen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorLarmonier, Nicolasen_US
dc.contributor.advisorKatsanis, Emmanuelen_US
dc.contributor.committeememberLarmonier, Nicolasen_US
dc.contributor.committeememberKatsanis, Emmanuelen_US
dc.contributor.committeememberHarris, Daviden_US
dc.contributor.committeememberHeimark, Ronalden_US
dc.contributor.committeememberLybarger, Lonnieen_US
dc.contributor.committeememberNelson, Marken_US
dc.identifier.proquest11530-
dc.identifier.oclc752261394-
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