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Novel mechanisms of cytokine signaling on T-cell and MDSC function in glioma development

Kohanbash, Gary (2012) Novel mechanisms of cytokine signaling on T-cell and MDSC function in glioma development. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Malignant gliomas are the most common primary brain tumors with dismal prognosis. A growing line of evidence supports significant roles of immunosurveillance for prevention and regulation of cancer development. For example, tumor infiltrating T-cells are capable of killing tumor cells and are a positive prognostic factor for cancer patients. T-cell immune responses are classified into distinct effector cell types, type-1 or type-2, based on their cytokine-secreting profiles. We have demonstrated that tumor-specific type-1 T-cells, but not type-2 T-cells, can efficiently traffic into CNS tumor sites and mediate effective therapeutic efficacy via a type-1 chemokine CXCL10 and an integrin receptor VLA-4. Despite the importance of the type-1 T cell response, cancers, including GBMs, secrete numerous type-2 cytokines that promote tumor proliferation and immune escape. The hallmark cytokines of type-1 and type-2 immune responses are IFNs and IL-4, respectively. We therefore sought to better understand the role of IL-4 and IFN signaling in gliomas. We herein demonstrate that the miR-17-92 cluster is down-regulated in T-cells in both human and mouse tumors, dependent on IL-4R signaling. Further, ectopic expression of miR-17-92 cluster in T-cells resulted in enhanced IFN-γ and IL-2 production and resistance to activation induced cell death (AICD) (Aim 1). We next examined IL-4Rα on immunosuppressive myeloid derived suppressor cells (MDSCs). Interestingly we found that IL-4Rα was up-regulated on human and mouse glioma infiltrating, but not peripheral, MDSCs. Additionally, IL-4Rα expression promoted arginase activity, T-cell suppressing abilities and glioma growth (Aim 2).
As type I IFNs are important for anti-glioma type-1 immunity, we further examined how type I IFNs impact glioma patient prognosis. As there are multiple type I IFNs, our collaborators assisted us to identify potentially important genes by single nucleotide polymorphism (SNP) analysis. We found that IFN-pathway genes IFN- alpha receptor-1 (IFNAR1) and the IFN-alpha-8 (IFNA8) promoter both had SNPs associated with glioma prognosis. By luciferase assay and electrophoretic mobility shift assay (EMSA) we demonstrated that the A-allele, which is associated with better glioma patient survival, but not the C-allele of rs12553612 in the promoter region of IFNA8 allows for OCT-1 binding and activity of the IFNA8 promoter (Aim 3).
Overall, our data suggests that type-2 promoting has a dual role in suppressing glioma immunity through decreased T-cell functioning and enhanced MDSC function. Type-2 promoted suppression of glioma immunity can thus lead to better glioma patient prognosis, a significant public health achievement.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Kohanbash, Garygkohanbash@gmail.com
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairOkada, Hidehookadah@upmc.edu
Committee CoChairMartinson, Jeremyjmartins@pitt.eduJMARTINS
Committee MemberKalsinski, Pawelkalinskip@upmc.eduPAK5
Committee MemberRobbins, Paulprobb@pitt.eduPROBB
Committee MemberChen, Yuecheny@pitt.eduCHENY
Thesis AdvisorOkada, Hidehookadah@upmc.edu
Date: 24 September 2012
Date Type: Publication
Defense Date: 19 June 2012
Approval Date: 24 September 2012
Submission Date: 27 June 2012
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Number of Pages: 166
Institution: University of Pittsburgh
Schools and Programs: Graduate School of Public Health > Infectious Diseases and Microbiology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: MicroRNA, T-cell, MDSC, glioma, GBM
Date Deposited: 24 Sep 2012 18:51
Last Modified: 24 Sep 2017 05:15
URI: http://d-scholarship.pitt.edu/id/eprint/13496

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