Link to the University of Pittsburgh Homepage
Link to the University Library System Homepage Link to the Contact Us Form

Modulation of tumoricidal activities of dendritic cells to enhance antigen uptake and cross-presentation

Huang, Jian (2005) Modulation of tumoricidal activities of dendritic cells to enhance antigen uptake and cross-presentation. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

Primary Text

Download (1MB) | Preview


Abstract Dendritic cells (DCs) are professional antigen-presenting cells that are integral to the induction of primary, antigen-specific T cell responses. In the cancer setting, DCs mediate cross-priming of tumor-reactive T cells by presenting tumor antigens acquired from viable or dead cancer cells. Due to their unique functional properties, DCs have been utilized as both vectors and targets for immunological intervention in numerous diseases and are optimal candidates for vaccination protocols in cancer. In addition to their antigen presentation function(s), recent evidence suggests that DCs may also perform an innate immune effector function, with human DCs reported to mediate direct tumoricidal activity in vitro. However, the mechanism(s) by which DCs directly kill tumor cells remain unclear. The goal of this study is to further characterize the mechanism(s) associated with murine DC tumoricidal function and to determine whether and how this function may be enhanced to promote anti-tumor immune responses that translate into therapeutic effectiveness. One way we sought to enhance this DC effector function was through the genetic engineering of DCs themselves. After transduction with mIL-12 and/or mIL-18 cDNA using recombinant adenoviral vectors, DCs exhibited significantly elevated tumor killing activity. This was mediated, at least in part, by TNF ligand-receptor complexes, as demonstrated by antibody blocking assays. When injected in situ, these engineered DCs exhibited prolonged survival, in association with enhanced levels of tumor apoptosis proximal to imaged DCs and our capacity to image DC that had engulfed tumor apoptotic bodies. We also observed notable therapeutic benefits upon intratumoral delivery of these DCs in concert with an expanded in vivo repertoire of anti-tumor CD8+ T cells. In addition to DC modification, we also evaluated treatments applied to tumor cells that resulted in enhanced sensitivity to (control) DC-mediated killing. Specifically, we found that pretreatment of A20 lymphoma cells with a nitric oxide (NO) donor compound, PAPA-NO, markedly increased the sensitivity of tumor cells to consequent apoptosis mediated by DCs. This appeared to provide DCs with a preferred source of tumor antigens, with which, they were capable of activating specific T cells via a cross-presentation pathway. We have also discovered that multiple TNF family ligands participated in DC-mediated tumoricidal function and that tumor cell-expressed survivin may represent a critical downstream factor regulating the apoptotic sensitivity of tumor cells to DC-mediated apoptosis. When taken together, these studies provide novel details regarding mechanisms involved in DC anti-tumor effector function, and suggest two DC-based, combinational cancer therapies that target the effective cross-priming of therapeutic T cells. The results presented in this dissertation support an efficient model in which DCs may not only serve as the gatherers and presenters of antigens, but also the hunters as well, with tumoricidal activity mediated via TNF family ligands.


Social Networking:
Share |


Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairStorkus, Walter Jstorkuswj@upmc.eduSTORKUSW
Committee MemberFalo, Louis Dfalold@upmc.eduLOF2
Committee MemberVujanovic, Nikola Lvujanovi@pitt.eduVUJANOVI
Committee MemberRobbins, Paul Dprobb@pitt.eduPROBB
Committee MemberChambers, William
Date: 9 December 2005
Date Type: Completion
Defense Date: 12 October 2005
Approval Date: 9 December 2005
Submission Date: 28 November 2005
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Immunology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: apoptosis; dendritic cells; IL-12; IL-18; nitric oxide; Tumor
Other ID:, etd-11282005-140434
Date Deposited: 10 Nov 2011 20:06
Last Modified: 19 Dec 2016 14:37


Monthly Views for the past 3 years

Plum Analytics

Actions (login required)

View Item View Item