Objective
Research objectives and content The proposed project involves studies to increase the immunogenicity of tumor cells by transfection with a foreign heat shock protein gene. Heat shock proteins (HSPs) are abundant proteins of different molecular weight classes which are present in the cytosol as well as in all cellular organelles. During various physiological processes such as protein synthesis, degradation and transport through membranes, they bind to interactive sites of polypeptides thereby preventing their improper interaction with other molecules and enabling controlled further processing of the polypeptide in question. Previous studies with the macrophage murine tumor cell line J774 have shown that ex vivo insertion of a gene coding the Mycobacterium leprae HSP65 kDa into the tumor cells results in their inability to form tumors in mice and generation of effective antitumor immunity, indicating that the presence of the mycobacterial HSP65 kDa enhanced immunological recognition of unique structures expressed by the tumor cell. The mechanisms by which highly conserved proteins like HSPs are involved in eliciting immune responses are not clear. However, it is suggested that HSPs may act as carrier molecules to present immunogenic peptides. To investigate this mechanism we have initially generated primary cytotoxic T lymphocytes (CTL) utilizing a murine allogeneic system in vitro, and tested these cells for cytotoxic activity against mycobacterial HSP65 kDa transfectants of the murine mastocytoma cell line P815. The work to date has involved transfection of P815 cells with the mycobacterial hsp65 gene in order to establish the target cell line, generation of cytotoxic T lymphocytes capable of recognizing P815 cells and optimising the cytotoxicity assay in which P815 cells are Iysed by cytotoxic T cells. The data from this preliminary study indicate that mycobacterial HSP65 expression on P815 transfectants results in a substantial increase of susceptibility to allospecific CI L lysis. Based on these results we are now conducting more extensive studies in order to evaluate the role of HSP65 kDa in the molecular mechanisms involved in the immunological recognition of the P815 tumor cell line. It is now proposed to determine whether HSP65 kDa could be increasing or altering processing and/or presentation of self-molecules such that they were more likely to be recognized by the irnmune system. Furthermore, it is also planned to investigate whether a cytotoxic immune response against exogenous antigens could be generated using gene therapy with the hsp65 kDa gene.
Training content (objective, benefit and expected impact)
The use of HSP for cancer immunotherapy is based on the physiological function of these proteins. They are chaperones which may play a role in the processing and/or presentation of antigens by binding to processed antigenic peptides and facilitating their interactions with the immune system. In this context, one could envision that tumour cells could be genetically modified to function as antigen presenting cells for tumor antigens. It is quite clear that additional studies are required to define precisely how genetically modified tumor cells stimulate immunity. They will hopefully be incorporated into the design of future tumor cell vaccines, and thereby further improve the therapeutic efficacy of genetically modified tumor cells for the treatment of malignancies. Links with industry / industrial relevance (22)
None at present, although a number of potential links are currently under negotiation.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques.
- medical and health sciencesmedical biotechnologygenetic engineeringgene therapy
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteins
- medical and health sciencesbasic medicinepharmacology and pharmacypharmaceutical drugsvaccines
- medical and health sciencesclinical medicineoncology
- medical and health sciencesbasic medicineimmunologyimmunotherapy
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Call for proposal
Data not availableFunding Scheme
RGI - Research grants (individual fellowships)Coordinator
NW7 1AA London
United Kingdom