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Nucleosome-releasing treatment makes surviving tumor cells better targets for nucleosome-specific anticancer
1Center for Imaging and Pharmaceutical Research, Massachusetts General Hospital and Harvard Medical School, Charlestown 02129-2060, USA.
Abstract:
Monoclonal antibody (MoAb) 2C5, a nucleosome-specific antinuclear autoantibody (ANA) from the repertoire of aged mice, was recently reported to recognize the surface of various tumor cells but not normal cells. Surface-bound nucleosomes (NSs) were previously proven to be MoAb 2C5's target on the outer membrane of tumor cells. Furthermore, MoAb 2C5 was found to have a strong antitumor effect during the early stages of tumor development. In an attempt to further increase antitumor effect of nucleosome-specific tumorocidal monoclonal antibody against established tumors, we investigated a possible way to enhance antibody association with tumor cells. Evidence is presented here demonstrating that the in vitro treatment of tumor cells (S49 T lymphoma) resulting in a partial cell death and massive liberation of intact NSs from dead tumor cells into the culture medium was accompanied by a 50-fold increase of MoAb 2C5 binding to the surface of surviving tumor cells. Massive NS release was observed in the case of S49 T-cell treatment with dexamethasone and vincristine. However, a partial cell killing that was not accompanied with NS release (EL4 lymphoma treatment with doxorubicin) did not result in the enhanced binding of MoAb 2C5 to the surface of surviving tumor cells. The use of NS-specific tumorocidal antibodies, such as MoAb 2C5, in combination with another NS release-inducing tumor therapy, should provide an enhanced antibody-tumor binding.
Insights
Monoclonal antibody (MoAb) 2C5 targets tumor cells by binding to surface-bound nucleosomes (NSs). Combining MoAb 2C5 with therapies that release NSs enhances antibody binding to established tumors.
Area of Science:
- Immunology
- Oncology
- Biochemistry
Background:
- Monoclonal antibody (MoAb) 2C5 is a nucleosome-specific autoantibody that targets tumor cells.
- MoAb 2C5 recognizes surface-bound nucleosomes (NSs) on tumor cells and exhibits antitumor effects in early-stage tumors.
- Enhancing MoAb 2C5 binding to established tumors is crucial for increasing its therapeutic efficacy.
Purpose of the Study:
- To investigate methods for enhancing the binding of MoAb 2C5 to established tumor cells.
- To determine if inducing nucleosome release from tumor cells increases MoAb 2C5 binding.
Main Methods:
- In vitro treatment of S49 T lymphoma and EL4 lymphoma cells with various agents (dexamethasone, vincristine, doxorubicin).
- Quantification of cell death and nucleosome (NS) release into the culture medium.
- Measurement of MoAb 2C5 binding to the surface of surviving tumor cells using flow cytometry.
Main Results:
- Treatment of S49 T lymphoma cells with dexamethasone or vincristine induced partial cell death and massive NS release, leading to a 50-fold increase in MoAb 2C5 binding to surviving cells.
- Treatment of EL4 lymphoma cells with doxorubicin caused partial cell killing without significant NS release, and did not enhance MoAb 2C5 binding.
- Enhanced MoAb 2C5 binding correlated directly with the extent of NS release.
Conclusions:
- Inducing nucleosome release from tumor cells is a viable strategy to enhance the binding of nucleosome-specific antibodies like MoAb 2C5.
- Combining MoAb 2C5 with therapies that promote NS release may improve treatment outcomes for established tumors.
- This approach offers a potential pathway for more effective antibody-based cancer immunotherapy.