Projects / Programmes
The regulation of the T cell functions by alpha-type 1–polarized (alphaDC1) and standard dendritic cells (sDCs)
| Code |
Science |
Field |
Subfield |
| 3.01.00 |
Medical sciences |
Microbiology and immunology |
|
| Code |
Science |
Field |
| B001 |
Biomedical sciences |
General biomedical sciences |
| Code |
Science |
Field |
| 3.05 |
Medical and Health Sciences |
Other medical sciences |
dendritic cells, lymphocytes T, homing, tumor, antitumor vaccines
Researchers (1)
| no. |
Code |
Name and surname |
Research area |
Role |
Period |
No. of publicationsNo. of publications |
| 1. |
25494 |
PhD Nataša Obermajer |
Biotechnology |
Head |
2010 - 2012 |
196 |
Organisations (1)
| no. |
Code |
Research organisation |
City |
Registration number |
No. of publicationsNo. of publications |
| 1. |
0106 |
Jožef Stefan Institute |
Ljubljana |
5051606000 |
90,753 |
Abstract
We propose to analyze the mechanism of the differential ability of ?DC1s and sDC to induce distinct homing receptor expression and activation in tumor-specific T cells, as the fourth dendritic cell (DC)-related signal essential for the efficacy of DC-based cancer vaccines. We will test the hypothesis that DCs maturing in different environments, in addition to their differential ability to induce type-1 versus type 2 responses (signal 3), can also differentially regulate the expression of chemokine and integrin receptors in tumor-specific T cells (signal 4), essential for the efficacy of DC based cancer vaccines.
DCs are increasingly applied as vaccines in experimental treatment for cancer patients. Several features of DCs, including their maturation status, migratory potential, and cytokine production, were shown important for the ability of DC-based cancer vaccines to induce high numbers of Th1-type CD4+ T cells and CD8+ CTLs. Effective induction of antitumor CTL responses requires fully mature DCs that express high levels of costimulatory molecules and that can migrate in response to lymph-node-produced CCR7 ligands. In addition, high interleukin- 12p70 (IL-12p70) secretion dramatically enhances the ability of DCs to induce tumor specific Th1 cells and CTLs, and promotes tumor rejection in therapeutic mouse models. The maturation stage of current “gold standard” DCs (sDCs) inversely correlates with their ability to produce IL-12p70. In attempt to boost the ability of DCs to induce anticancer responses, novel culture procedures have been developed yielding DCs that combine, within a single cell, three features important for their efficacy as carriers of anticancer vaccines: (a) fully mature status; (b) high migratory responsiveness to lymph-node associated chemokines (CCR7 ligands); and (c) ability to produce high levels of IL-12p70.
The migration of leukocytes is a multistep process mediated by a series of cellular molecular interactions. The requirement for adhesion molecules in this process has been acknowledged. In the T cells, it has been proposed that chemokines serve to activate T cell integrins and allow them to mediate firm binding to the vascular adhesion molecules such as VCAM-1 and ICAM1-1. This regulation depends on the ability of chemokines to induce affinity modulation of ß2 and ß1 integrin adhesion molecules expressed on lymphocytes and facilitate lymphocyte binding to EC and to immobilized ligands. In this regard, T cells should bear chemokine receptors for the implementation of integrin function.
Distinct chemokine profiles are imprinted in DCs during their maturation and are preserved in mature DCs after their removal from different inflammatory environment. Type-1 polarized DCs (?DC1s) show selectively enhanced ability to induce functional Th1 and CTL (Teff) cells, when compared to the current “standard” of clinically-used DCs (sDC). Preliminary data demonstrate that ?DC1s and sDC induce different sets of T cell-associated chemokine receptors (CKRs), with ?DC1s being superior in inducing CXCR3 and CCR5, the CKRs implicated in tumor-entry of melanoma-specific T cells. There is a correlation of CCR5 expression and LFA-1 function and it has been suggested that IL-12 functions to upregulate CCR5-mediated LFA-1 activation. As well, ?DC1s and sDC show induction of different sets of T cell-associated homing receptors, with ?DC1s being superior in inducing cutaneous lymphocyte antigen (CLA), a skin lymphocyte homing receptor, whereas sDC are superior in inducing ?4ß7, a gut homing receptor, however the expression of some other adhesion molecules in not significantly affected. Moreover, the addition of rhIL-12 to DC-T cell cultures enhances the expression of CLA, whereas it decreases the expression of ?4ß7. The difference in the expression of these homing receptors by T cells may prove to have functional relevance for the efficacy of ?DC1 vs sDC-based vaccines in different types of tumors.
Significance for science
Despite the introduction of novel biological drugs for the treatment of cancer and immunedysfunctional
diseases, there is a need for specific biological cell-based therapies, that would
allow for highly efficient antitumor immune activation and recognition of tumor antigens. The
main challenge so far has been to generate highly functional DCs with ability to induce strong
Th1 cells and CTLs (the types of immune cells most desirable in cancer immunotherapy) in vivo
and ex vivo with concommitant prevention of immunosuppressive part of tumor-induced
immune responses. Since the development of these therapies is in its very beginnings, we
believe that the acceptance of our group and achievements among the state-of the art laboratories in developed world is a great opportunity and honour. We have established a
collaboration with the group of Prof. Dr. Pawel Kalinski at Hillman Cancer Center, University of
Pittsburgh, USA. Based on the results of our collaboration, Nataša Obermajer was selected as a
speaker at two highly-ranked international conferences (AACR annual meeting, Orlando and AAI
annual meeting, San Francisco).
Significance for the country
Broad area of experimental pharmacy and medicine in R Slovenia is well developed. We
managed to transfer a part of the technological development in the last ten years in application,
in particular some alternative methods of treatment and development of new drugs. Despite
some economical barriers the current therapy of cancer patients follows the EU guidelines,
being a standard in contemporary praxis. We are aware of the long lasting procedures needed
for the transfer of the knowledge and technology in medicine and pharmacy, however based on
the current results, gained in 2010, we prepared a patent application for the method of
generation of dendritic cell and their use in therapy. The tradition in research and development
of technologies in medicine and accesability of samples are a true advantage in introduction of
nre technologies in R Slovenia, EU and else. At the end of this project, with the promising
results, we will consider to establish a 'start up' unit, that would allow faster transfer of
technology from its experimental phase.
Most important scientific results
Annual report
2010,
2011,
final report,
complete report on dLib.si
Most important socioeconomically and culturally relevant results
Annual report
2010,
2011,
final report,
complete report on dLib.si
