Disruption of Transforming Growth Factor-beta Signaling Using a Small Molecule TGF-beta Receptor Type I Kinase Inhibitor Improves the Efficacy of Dendritic Cell Vaccines

Persistent Link:
http://hdl.handle.net/10150/194430
Title:
Disruption of Transforming Growth Factor-beta Signaling Using a Small Molecule TGF-beta Receptor Type I Kinase Inhibitor Improves the Efficacy of Dendritic Cell Vaccines
Author:
Rausch, Matthew Peter
Issue Date:
2008
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.
Abstract:
Immunotherapy has been proposed as an alternative to conventional cancer therapies due to its reduced toxicity and ability to induce long-lasting anti-tumor immune responses. Dendritic cell (DC) vaccination is one immune-based anti-cancer strategy that has received attention due to the ability of DC to process and present antigen to T lymphocytes to initiate immune responses. However, the clinical efficacy of DC-based immunotherapy against established cancers in humans has been extremely low and despite recent advances, objective response rates in DC vaccine trials are rarely above 10%. This lack of efficacy is due in part to immunosuppressive factors, such as transforming growth factor &beta (TGF-&beta), present in the tumor microenvironment that promote tumor immune escape. Therefore, TGF-&beta represents a major barrier to effective cancer immunotherapy and strategies to neutralize this cytokine may lead to more efficacious DC vaccines.In this study, we employed two small molecule transforming growth factor &beta receptor type I (T&betaRI/ALK5) kinase inhibitors (HTS466284 and SM16) in combination with DC vaccines to treat established TGF-&beta-secreting 4T1 mammary tumors. The results demonstrate that while both inhibitors blocked the effects of TGF-&beta in vitro, HTS466284 by itself or in combination with DC vaccination was unable to consistently control the growth and metastasis of established 4T1 tumors. In contrast, SM16 inhibited the growth of established tumors when delivered orally and suppressed the formation of pulmonary metastases when delivered orally or via daily intraperitoneal (i.p.) injection. The efficacy of SM16 was dependent on cellular immunity as this drug had no effect in immunodeficient SCID mice. Furthermore, orally delivered SM16 in combination with DC vaccination led to complete tumor regression in several mice that correlated with increased T cell infiltration of the primary tumor and enhanced in vitro IFN-gamma production and tumor-specific cytolytic activity by splenocytes. Finally, a suboptimal dose of SM16 that failed to control primary tumor growth on its own synergized with DC vaccination to inhibit the growth of established 4T1 tumors. These findings suggest that blockade of TGF-&beta signaling using a small molecule T&betaRI/ALK5 kinase antagonist may be an effective strategy to bolster the efficacy of DC-based cancer vaccines.
Type:
text; Electronic Dissertation
Keywords:
Breast Cancer; Dendritic Cell; Immunotherapy; Small Molecule Kinase Inhibitor; Transforming Growth Factor Beta
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Microbiology & Immunology; Graduate College
Degree Grantor:
University of Arizona
Advisor:
Akporiaye, Emmanuel T.
Committee Chair:
Akporiaye, Emmanuel T.

Full metadata record

DC FieldValue Language
dc.language.isoenen_US
dc.titleDisruption of Transforming Growth Factor-beta Signaling Using a Small Molecule TGF-beta Receptor Type I Kinase Inhibitor Improves the Efficacy of Dendritic Cell Vaccinesen_US
dc.creatorRausch, Matthew Peteren_US
dc.contributor.authorRausch, Matthew Peteren_US
dc.date.issued2008en_US
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.abstractImmunotherapy has been proposed as an alternative to conventional cancer therapies due to its reduced toxicity and ability to induce long-lasting anti-tumor immune responses. Dendritic cell (DC) vaccination is one immune-based anti-cancer strategy that has received attention due to the ability of DC to process and present antigen to T lymphocytes to initiate immune responses. However, the clinical efficacy of DC-based immunotherapy against established cancers in humans has been extremely low and despite recent advances, objective response rates in DC vaccine trials are rarely above 10%. This lack of efficacy is due in part to immunosuppressive factors, such as transforming growth factor &beta (TGF-&beta), present in the tumor microenvironment that promote tumor immune escape. Therefore, TGF-&beta represents a major barrier to effective cancer immunotherapy and strategies to neutralize this cytokine may lead to more efficacious DC vaccines.In this study, we employed two small molecule transforming growth factor &beta receptor type I (T&betaRI/ALK5) kinase inhibitors (HTS466284 and SM16) in combination with DC vaccines to treat established TGF-&beta-secreting 4T1 mammary tumors. The results demonstrate that while both inhibitors blocked the effects of TGF-&beta in vitro, HTS466284 by itself or in combination with DC vaccination was unable to consistently control the growth and metastasis of established 4T1 tumors. In contrast, SM16 inhibited the growth of established tumors when delivered orally and suppressed the formation of pulmonary metastases when delivered orally or via daily intraperitoneal (i.p.) injection. The efficacy of SM16 was dependent on cellular immunity as this drug had no effect in immunodeficient SCID mice. Furthermore, orally delivered SM16 in combination with DC vaccination led to complete tumor regression in several mice that correlated with increased T cell infiltration of the primary tumor and enhanced in vitro IFN-gamma production and tumor-specific cytolytic activity by splenocytes. Finally, a suboptimal dose of SM16 that failed to control primary tumor growth on its own synergized with DC vaccination to inhibit the growth of established 4T1 tumors. These findings suggest that blockade of TGF-&beta signaling using a small molecule T&betaRI/ALK5 kinase antagonist may be an effective strategy to bolster the efficacy of DC-based cancer vaccines.en_US
dc.typetexten_US
dc.typeElectronic Dissertationen_US
dc.subjectBreast Canceren_US
dc.subjectDendritic Cellen_US
dc.subjectImmunotherapyen_US
dc.subjectSmall Molecule Kinase Inhibitoren_US
dc.subjectTransforming Growth Factor Betaen_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplineMicrobiology & Immunologyen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorAkporiaye, Emmanuel T.en_US
dc.contributor.chairAkporiaye, Emmanuel T.en_US
dc.contributor.committeememberKatsanis, Emmanuelen_US
dc.contributor.committeememberBernstein, Harrisen_US
dc.contributor.committeememberLybarger, Lonnieen_US
dc.contributor.committeememberBowden, Timothyen_US
dc.identifier.proquest10201en_US
dc.identifier.oclc659753419en_US
All Items in UA Campus Repository are protected by copyright, with all rights reserved, unless otherwise indicated.