Doxorubicin and T Helper Lymphocytes: Unexpected Allies Against Cancer

Persistent Link:
http://hdl.handle.net/10150/307049
Title:
Doxorubicin and T Helper Lymphocytes: Unexpected Allies Against Cancer
Author:
Alizadeh, Darya
Issue Date:
2013
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:
Despite considerable progress in conventional cancer therapies, major challenges persist in the treatment of patients with advanced stage malignancies. Cancer immunotherapy (harnessing the immune system against tumors) has demonstrated limited success to date, partially due to the immunosuppressive environment generated by tumors. The mechanisms of cancer-induced immune suppression are multiple and include the promotion of immunosuppressive cells such as regulatory T cells (Treg) and myeloid-derived suppressor cells (MDSC). MDSC expand in tumor-bearing hosts and play a central role in cancer immune evasion by inhibiting adaptive and innate immunity. Different approaches have been explored to negatively impact MDSC, each associated with specific pitfalls. In this study, we demonstrated that the anthracycline doxorubicin selectively eliminates MDSC in the spleen, blood and tumor beds. Furthermore, five days after doxorubicin treatment residual MDSC exhibited impaired suppressive function, which correlated with reduced reactive oxygen species (ROS) production, and down-regulation of arginase-1 and indoleamine 2,3-dioxygenase (IDO) expression. Of therapeutic relevance, the frequency of effector lymphocytes (CD4⁺ and CD8⁺ T cells) or natural killer cells (NK) to suppressive MDSC ratios was significantly increased following doxorubicin treatment of tumor-bearing mice. Importantly, the proportion of natural killer (NK) and cytotoxic T cells (CTL) expressing perforin and granzyme B and of CTL producing IFNγ was augmented following doxorubicin administration. The mechanism of doxorubicin-mediated elimination of MDSC was partly mediated by the increase of ROS production in MDSC at earlier time points after doxorubicin treatment. Consistently, MDSC isolated from gp91-/- mice were less sensitive to doxorubicin in vitro, and doxorubicin effects on MDSC in gp91-/- tumor-bearing mice were reduced. Of clinical significance, this drug efficiently combined with Th1 or Th17 lymphocytes to suppress tumor development and metastatic disease, resulting in better overall survival. MDSC isolated from patients with different types of cancer were also sensitive to doxorubicin-mediated cytotoxicity in vitro. Our results therefore indicate that doxorubicin may be used not only as a direct cytotoxic drug against tumor cells, but also as a potent immunomodulatory agent that selectively impairs MDSC-induced immunosuppression, thereby fostering the efficacy of T cell-based immunotherapy.
Type:
text; Electronic Dissertation
Keywords:
Cancer Biology
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Graduate College; Cancer Biology
Degree Grantor:
University of Arizona
Advisor:
Larmonier, Nicolas; Katsanis, Emmanuel

Full metadata record

DC FieldValue Language
dc.language.isoen_USen_US
dc.titleDoxorubicin and T Helper Lymphocytes: Unexpected Allies Against Canceren_US
dc.creatorAlizadeh, Daryaen_US
dc.contributor.authorAlizadeh, Daryaen_US
dc.date.issued2013-
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.abstractDespite considerable progress in conventional cancer therapies, major challenges persist in the treatment of patients with advanced stage malignancies. Cancer immunotherapy (harnessing the immune system against tumors) has demonstrated limited success to date, partially due to the immunosuppressive environment generated by tumors. The mechanisms of cancer-induced immune suppression are multiple and include the promotion of immunosuppressive cells such as regulatory T cells (Treg) and myeloid-derived suppressor cells (MDSC). MDSC expand in tumor-bearing hosts and play a central role in cancer immune evasion by inhibiting adaptive and innate immunity. Different approaches have been explored to negatively impact MDSC, each associated with specific pitfalls. In this study, we demonstrated that the anthracycline doxorubicin selectively eliminates MDSC in the spleen, blood and tumor beds. Furthermore, five days after doxorubicin treatment residual MDSC exhibited impaired suppressive function, which correlated with reduced reactive oxygen species (ROS) production, and down-regulation of arginase-1 and indoleamine 2,3-dioxygenase (IDO) expression. Of therapeutic relevance, the frequency of effector lymphocytes (CD4⁺ and CD8⁺ T cells) or natural killer cells (NK) to suppressive MDSC ratios was significantly increased following doxorubicin treatment of tumor-bearing mice. Importantly, the proportion of natural killer (NK) and cytotoxic T cells (CTL) expressing perforin and granzyme B and of CTL producing IFNγ was augmented following doxorubicin administration. The mechanism of doxorubicin-mediated elimination of MDSC was partly mediated by the increase of ROS production in MDSC at earlier time points after doxorubicin treatment. Consistently, MDSC isolated from gp91-/- mice were less sensitive to doxorubicin in vitro, and doxorubicin effects on MDSC in gp91-/- tumor-bearing mice were reduced. Of clinical significance, this drug efficiently combined with Th1 or Th17 lymphocytes to suppress tumor development and metastatic disease, resulting in better overall survival. MDSC isolated from patients with different types of cancer were also sensitive to doxorubicin-mediated cytotoxicity in vitro. Our results therefore indicate that doxorubicin may be used not only as a direct cytotoxic drug against tumor cells, but also as a potent immunomodulatory agent that selectively impairs MDSC-induced immunosuppression, thereby fostering the efficacy of T cell-based immunotherapy.en_US
dc.typetexten_US
dc.typeElectronic Dissertationen_US
dc.subjectCancer Biologyen_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.disciplineCancer Biologyen_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.committeememberNelson, Marken_US
dc.contributor.committeememberHeimark, Ronald L.en_US
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