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A melanosomal membrane protein is a cell surface target for melanoma therapy
Y Takechi1, I Hara, C Naftzger
1The Swim Across America Laboratory, Memorial Sloan-Kettering Cancer Center, and Cornell University Medical College, New York, NY 10021, USA.
Abstract:
Differentiation antigens on cancer cells are recognized by the immune system. A prototype set of these autoantigens in melanoma cells are the melanosomal glycoproteins, expressed in both melanomas and normal melanocytes. These are intracellular proteins that can be recognized by both antibodies and T lymphocytes. While one can understand how T cells can respond to intracellular proteins, based on cellular requirements for antigen processing and presentation, it is more difficult to understand how antibody responses to melanosomal proteins could lead to tumor rejection. We demonstrate that gp75 is expressed on the cell surface as well as intracellularly in human and mouse melanomas. The surface expression of gp75 can be augmented by IFN-gamma and during tumor growth in vivo. Surface expression of gp75 on mouse melanoma cells correlates with the ability of a monoclonal antibody (mAb) against gp75 to reject melanomas in syngeneic mice. Antibody-mediated rejection seems to require the Fc portion of the antibody, suggesting a role for Fc receptor-positive effector cells such as natural killer cells. However, although NK1.1(+) cells have been implicated in antibody-induced rejection in vivo, cell surface expression of gp75(+) on melanoma does not lead to susceptibility to antibody-dependent cellular cytotoxicity in vitro. The mAb to gp75 induced tumor rejection in mice carrying both scid and bg/bg traits, showing that neither thymus-dependent T cells nor natural killer cytotoxic activity was required in vivo. Long-term treatment of mice with mAb led to patchy depigmentation in the coat. In summary, an intracellular organellar protein can be expressed at the cell surface and provide an antigenic target for antibody therapy and autoimmunity.
Insights
An intracellular protein, gp75, is found on melanoma cell surfaces, enabling antibody therapy. This discovery opens new avenues for cancer treatment by targeting cell surface antigens.
Area of Science:
- Immunology
- Oncology
- Biochemistry
Background:
- Melanoma cells express differentiation antigens, including melanosomal glycoproteins, recognized by the immune system.
- Intracellular proteins typically require processing for T cell recognition, making antibody responses to them less understood for tumor rejection.
Purpose of the Study:
- To investigate the cell surface expression of gp75 in melanomas.
- To determine if surface-expressed gp75 can be a target for antibody-mediated tumor rejection.
Main Methods:
- Demonstrated gp75 cell surface expression in human and mouse melanomas.
- Augmented surface gp75 expression using IFN-gamma and in vivo tumor growth.
- Utilized monoclonal antibodies (mAbs) against gp75 in syngeneic mouse models.
- Assessed antibody-mediated rejection in immunodeficient mice (scid and bg/bg).
Main Results:
- Gp75 is expressed intracellularly and on the cell surface of melanomas.
- Surface gp75 expression is enhanced by IFN-gamma and during tumor growth.
- Monoclonal antibody against gp75 mediated melanoma rejection in mice.
- Tumor rejection occurred independently of T cells and natural killer cell cytotoxicity in specific mouse models.
Conclusions:
- Intracellular organellar proteins can be expressed on the cell surface, serving as targets for antibody therapy.
- Surface expression of gp75 provides a viable antigenic target for antibody-mediated cancer immunotherapy.
- This mechanism suggests potential for inducing autoimmunity against cancer cells via antibody targeting.