ANTIGEN PROCESSING AND IMMUNE RECOGNITION OF MELANOMA
Melanoma is the most lethal form of skin cancer and is resistant to existing chemotherapeutic agents. Immunotherapy holds great promise in the treatment of metastatic melanoma because melanoma antigens have been identified and patients generate T and B cell responses specific for these antigens which in some cases lead to spontaneous remission. Effective immunotherapy requires presentation of tumor antigens in the context of MHC class II for the activation of CD4+ T lymphocytes to generate and sustain the anti-tumor immune response. My laboratory is interested in understanding the role of MHC class II-restricted antigen processing components, in particular gamma-interferon inducible lysosomal thiol reductase (GILT), in the development of an effective immune response against melanoma.
Melanocyte differentiation antigens, including tyrosinase, tyrosinase-related protein (TRP)-1, TRP-2 and pmel-17/gp100, are present in both benign melanocytes and melanoma cells. They are melanosomal integral membrane proteins involved in pigment (melanin) biosynthesis. These proteins contain a dileucine-based sorting signal which serves to target these antigens to the endocytic pathway leading to presentation by MHC class II. Recently, we determined that GILT is essential for the class II-restricted processing of a certain TRP-1 epitope in vitro. Furthermore, in a mouse model of auto-immune destruction of melanocytes (vitiligo), the absence of GILT delays the onset of disease.
We are beginning to elucidate key elements in the pathogenesis of auto-immune vitiligo. Additionally, since many melanoma antigens represent self-antigens present in melanocytes, a productive anti-tumor response requires the avoidance of tolerance mechanisms which suppress the immune response to self-antigens. We are investigating the role of GILT in generating tolerance to self-antigens. We plan to extend these studies by evaluating the overall immune response and protection from melanoma following various cancer vaccination strategies in a mouse model.
These studies will identify key features of antigen processing required to generate an immune response to melanoma and may aid in the understanding of mechanisms that lead to immune evasion. The long-term goal of these studies is to aid the development of effective immunotherapy for melanoma.