Related Experiment Videos
Stressed apoptotic tumor cells express heat shock proteins and elicit tumor-specific immunity
1Department of Pediatrics, Steele Memorial Children's Research Center, University of Arizona, 1501 N. Campbell Ave., Tucson, AZ 85724, USA.
Abstract:
In attempting to develop effective anticancer immunotherapies, the relative ability of apoptotic cells to induce an immune response remains an important but controversial consideration. A novel gene-transfer approach was used by which rapid induction of pure apoptosis can be selectively achieved in a transfected tumor cell population following exposure to a semisynthetic dimerizing ligand, AP20187. Inoculation of BALB/c mice with apoptotic and viable 12B1-D1 leukemia cells, at a 12:1 ratio subcutaneously, led to early tumor growth. Heat stress up-regulated the expression of membrane heat shock proteins (HSP72 and HSP60) on apoptotic 12B1-D1 cells, and stressed apoptotic cells were capable of generating a T-cell-mediated specific antitumor response. Pulsing of stressed apoptotic leukemia cells onto syngeneic dendritic cells resulted largely in rejection of coinjected viable 12B1-D1 cells. Mice rejecting the primary 12B1-D1 inoculum were immune to the same but not to a different leukemia challenge. Our findings indicate that tumor immunogenicity is dependent on whether cells are stressed before apoptosis induction and suggest that the immune system is capable of distinguishing between stressed and nonstressed cells undergoing programmed cell death. (Blood. 2001;97:3505-3512)
Insights
Stressed apoptotic tumor cells, but not non-stressed ones, can induce a T-cell-mediated antitumor response. This finding suggests that tumor immunogenicity depends on cellular stress before programmed cell death, impacting anticancer immunotherapy development.
Area of Science:
- Immunology
- Oncology
- Cell Biology
Background:
- The role of apoptotic cells in inducing immune responses for anticancer immunotherapy is debated.
- Developing effective immunotherapies requires understanding how dying cancer cells interact with the immune system.
Purpose of the Study:
- To investigate if cellular stress influences the immunogenicity of apoptotic tumor cells.
- To explore a novel gene-transfer method for inducing apoptosis in tumor cells.
Main Methods:
- Utilized a gene-transfer approach with AP20187 to induce apoptosis in transfected tumor cells.
- Applied heat stress to up-regulate heat shock proteins (HSP72, HSP60) on apoptotic cells.
- Inoculated mice with stressed and non-stressed apoptotic and viable leukemia cells.
Main Results:
- Early tumor growth observed with non-stressed apoptotic and viable leukemia cells.
- Stressed apoptotic cells induced a T-cell-mediated specific antitumor response.
- Dendritic cell pulsing with stressed apoptotic cells led to rejection of viable tumor cells.
- Mice rejecting primary tumors showed specific immunity against the same leukemia type.
Conclusions:
- Tumor immunogenicity is contingent on cellular stress preceding apoptosis induction.
- The immune system can differentiate between stressed and non-stressed cells undergoing programmed cell death.
- Findings suggest strategies for enhancing anticancer immunotherapies by modulating cellular stress.