Dendritic Cells & Cancer
Staff
Funding
Collaborators
Student Projects
Key Recent Publications
Go to Glossary
Lab Head: Associate Professor Alejandro Lopez
Dendritic Cells (DC) are the key initiators and organizers of the immune response. They are responsible for inducing antigen specific recognition upon vaccination and therefore, ideal vehicles to deliver strong immunogenic signals to eliminate tumours. This important potential is now being harnessed for novel immunotherapy approaches against cancer. Our research has shown that DC are defective in cancer. In particular, we have demonstrated that patients with breast cancer carry dysfunctional DC in their blood (Publication 3, 4) and an increased number of DC die (from apoptosis) spontaneusly (Pubication 5) yielding a reduced number of DC in circulation (Publication 9).
The use of DC in the therapy of melanoma, prostate cancer and glioblastoma has shown great promise in work performed at the QIMR (Publication 10). The most striking results from the literature come from the first reproducible and long lasting success in the treatment of advanced melanoma with DC immunotherapy. This has been achieved by a collaborative project between the group of Dr Chris Schmidt and Prof Kay Ellem at the QIMR and Dr. Michael O'Rourke at the Mater Adult Hospital. This team obtained an average 15% complete remissions (CR) lasting for over five years in two consecutive and independent clinical trials performed on Stage IV melanoma patients. This unique finding is a first in the field of melanoma therapy and represents a valuable resource for the investigation of the mechanisms by which DC act in the treatment of cancer.
We established a very close collaborative effort with the group of Dr. Chris Schmidt focused on the use DC for cancer immunotherapy covering thee main areas of research:
1. Novel DC-based Immunotherapy for Breast Cancer
Growing interest on the function of stem cells at the origin of cancer has started from pionnering work on adult stem cells
of the central nervous system. Culture conditions generating spheres from these tissues yield cells with stem cell properties.
These techniques, developed amongst other by our collaborator Brent Reynolds, have been applied to breast cancer tissues.
This approach has generated cells with stem cells properties that we currently characterise. While it is still uncertain
if all cells in a tumour are derived from cancer stem cells, it has been demonstrated that they are indeed present in a
variety of tumours. Indeed, they appear to exist in breast and prostate cancer and brain tumours. Cancer stem cells have
all the properties of proliferating cells, including their acquired drug resistance qualities that might ensure their survival.
Hence, harvesting cancer stem cells for immunotherapy is quite an attractive possibility. In collaboration with Brent Reynolds
from the McKnight Brain Institute, University of Florida, Gainesville, USA and Sunil Lakhani from the
Molecular
Pathology Laboratory at QIMR we are currently studying the properties of "mammospheres" as breast cancer antigens for DC immunotherapy.
We have now derived mammospheres from primary tumours and breast cancer cell lines and are currently studying the immunological and tumour-generating properties. (Figure 1)
2. The biological potential of cancer stem cells
We are currently investigating the generation of cancer stem cells from other tissues including the melanoma, prostate cancer and glioblastoma. The project aims at understanding the biological and immunological properties of these cells that could be targeted for novel therapies. Similar techniques to those applied to the study of breast cancer stem cells have now yielded the possibility to investigate sphere forming cells derived from other cancer tissues. We study in vivo animal models to reproduce the tumourogenic potential of cancer stem cells.
3. Evaluation of the antigen presentation pathways used by DC
Cross presentation of tumour antigens, either in the form of soluble proteins or fragments of tumours appears to be an important part of the immune response to tumours. Using cytoplasmic and membrane labels we evaluate the interaction between tumour cells and DC. This mechanism is crucial in achieving immune recognition upon immunization with tumour cells. We are investigating the mechanisms involved in the presentation of tumour antigens in the sucessful DC-based protocols for melanoma treatment.
In order to understand the antigen presentation mechanisms, we studied a model for cross-presentation based on a soluble protein, a malaria vaccine candidate. This synthetic polypeptide (101 amino acid long) was shown to be efficiently cross-presented to T- cells (publication 1). Together with Dr Giampietro Corradin (Lausanne University) we investigate the pathways of antigen presentation and the particular requirements for best antigenicity (publication 6).
In order to investigate the application of these findings to tumour immunotherapy and in an animal model, we are collaborating with
the Immunovirology Laboratory led by Professor Andreas Suhrbier at QIMR.
Staff
| Labhead: | Associate Professor J. Alejandro Lopez |
| PhD Scholar: | Brian Morrison Imogen Guillions |
| Visiting Student: | Rebecca Johnston (3rd year Science, Griffith University) |
To see staff contact details, please type name below and hit Enter
Funding
National Breast Cancer Foundation
Griffith University
Queensland University of Technology
The University of Queensland
Collaborators
Dr Chris Schmidt (Cancer Immunotherapy Laboratory, QIMR)
Professor Sunil Lakhani (Molecular Pathology Laboratory, QIMR)
Professor Andreas Suhrbier (Immunovirology Laboratory, QIMR)
Dr Brent Reynolds (Queensland Brain Institute, The University of Queensland
Dr Colin Furnival (Royal Brisbane Hospital/Wesley Medical Centre)
Dr Chris Pyke (Mater Adult Hospital)
Dr Derek Kennedy (Eskitis Institute, Griffith University)
Professor Hans-Acha Orbea (Université de Lausanne, Switzerland)
Associate Professor Michael McGuckin (Mater Medical Research Institute)
Dr Giampietro Corradin (Université de Lausanne, Switzerland)
Professor Vasso Apostolopoulos and Professor Geoff Pieterz (Austin Research Institute)
Dr Arturo Londoño-Vallejo (INSERM Unit 434, Paris)
Student Projects
Research projects for students are available within the Dendritic Cell and Cancer Laboratory for BSc Honours, MMedSci and PhD students interested in working on the function of DC in Cancer.
Key Publications
B.J. Morrison, C.W. Schmidt, S.R. Lakhani, B.A. Reynolds and J. A. López (2008). “Breast Cancer Stem Cells: Implications for Therapy of Breast Cancer”. Breast Cancer Research. 10: 210. [Free PDF]
1. S. Prato, T. Maxwell, A. Pinzón-Charry, C.W. Schmidt, G. Corradin and J.A. López. (2005). "MHC class I-restricted exogenous presentation of a synthetic 102-mer malaria vaccine polypeptide". European Journal of Immunology. 35(3):681-89 [pubmed abstract]
2. Pinzon-Charry, T. Maxwell and J.A. López. (2005) "Dendritic Cell Dysfunction in Cancer: A Mechanism for Immunosuppression". Immunology and Cell Biology. 83(5):451-61 [pubmed abstract]
3. Pinzon-Charry, C.S. Ho, R. Laherty, T. Maxwell, D. Walker, R.A. Gardiner, L. O'Connor, C. Pyke, C.W. Schmidt, C. Furnival and J.A. López. (2005). "A Population of HLA-DR+ Immature Cells Accumulate in the Blood Dendritic Cell Compartment of Patients with Different Types of Cancer". Neoplasia. 7(12): 1123-32 [free on-line PDF available]
4. Pinzon-Charry, T. Maxwell, S. Prato, C. Furnival, C.W. Schmidt and J.A. López. (2005). "HLA-DR+ Immature Cells Exhibit Reduced Antigen Presenting Cell Function but Respond to CD40 Stimulation". Neoplasia. 7(12):1112-22 [free on-line PDF available]
5. Pinzon-Charry, T. Maxwell, M.A. McGuckin, C.W. Schmidt, C. Furnival and J.A. López. (2006). "Spontaneous Apoptosis of Blood Dendritic Cells in Patients with Breast Cancer". Breast Cancer Research. 8(1):R5 [free on-line PDF available]
6. S. Prato, J. Fleming, C.W. Schmidt, G. Corradin and J.A. López. (2006). "Cross-presentation of a Human Malaria CTL Epitope is Conformation Dependent". Molecular Immunology. 43: (in press)
7.A. Pinzon-Charry, C.W. Schmidt and J.A. López. (2006). "The key role of CD40L in overcoming tumor-induced dendritic cell dysfunction. Breast Cancer Research". 8 (1): 402-403 [free on-line PDF available]
8. A. Pinzon-Charry, C.W. Schmidt and J.A. López. (2006). “Dendritic cell-based Immunotherapy for Breast cancer”. Expert Opinion on Biological Therapy. 6 (6):591-604 [pubmed abstract]
9. A. Pinzon-Charry, C.S. Ho, T. Maxwell, M.A. McGuckin, C.W. Schmidt, C. Furnival, C. Pyke, and J.A. López (2007). "Numerical and functional defects of blood dendritic cells in early and late stage breast Cancer". British Journal of Cancer. 97(9):1251-9 [on-line version]
10. M.G.E. O'Rourke, M.K. Johnson, C.M. Lanagan, J.L. See, L.E. O'Connor, G.J. Slater, D. Thomas, J. A. Lopez, N.R. Martinez, K.A.O. Ellem and C. W.Schmidt. (2007). "Dendritic Cell Immunotherapy for Stage IV Melanoma". Melanoma Research. 17: (5):316-22 [pubmed abstract]