Role of the ERAD pathway in the degradation of tyrosinase and production of antigenic peptides in human melanoma

Responsible applicant and co-applicants:

Romero Pedro, Division d'Onco-Immunologie Clinique Centre Ludwig, Université de Lausanne, Hôpital Orthopédique - CHUV

Petrescu Stefana, Institute of Biochemistry, Romanian Academy

A detailed knowledge of the mechanisms of antigen processing and presentation is essential to optimize cancer vaccination. known as Endoplasmic Reticulum Associated Degradation (ERAD). Non cytosolic misfolded proteins, synthesized at the endoplasmic reticulum are degraded to peptides by a complex machinery Cancer immunotherapy aims at harnessing the resources of the immune system to treat cancer. T lymphocytes, responsible for adaptive immune responses, can control and even eliminate large established tumors. The identification of the targets of anti-tumor T cell responses has provided the foundation to develop therapeutic cancer vaccines as well as cellular therapies by adoptive transfer of tumor reactive T cells. Hundreds of tumor antigens recognized by cytolytic CD8 T lymphocytes have been identified in recent years. These are short peptides derived from cellular proteins present in the cytosol. The majority of tumor antigens are in fact derived from normal protein components of cells and maybe present in normal tissues in addition to tumor cells. Such proteins undergo degradation in the cytosol. The resulting peptide fragments are actively transported into the endoplasmic reticulum where they associate with molecules of the Major Histocompatibility Complex (MHC) to form the mature tumor antigen. The non-covalent peptide/MHC complex is then transported to the cell surface where it is displayed for recognition by antigen-specific tumor reactive CD8 T cells. Non cytosolic misfolded proteins, synthesized at the endoplasmic reticulum are degraded to peptides by a complex machinery known as Endoplasmic Reticulum Associated Degradation (ERAD). A detailed knowledge of the mechanisms of antigen processing and presentation is essential to optimize cancer vaccination.

This project focuses on the study of the ERAD system. The Romanian partner is an expert biochemist who has made seminal contributions to the understanding of the role of ERAD in the trimming of peptides derived from the glycoprotein tyrosinase. This molecule is the rate limiting enzyme in the synthesis of melanin, the pigment made and distributed by melanocytes in the skin. In turn, melanocytes give rise to aggressive skin tumors, malignant melanoma, when transformed due in part to ultraviolet irradiation. Tyrosinase is also the source of a major melanoma tumor antigen that is recognized by human cytolytic CD8 T lymphocytes in patients with a growing melanoma tumor. The Swiss partner is an expert immunologist who focuses on the study of T cell responses to tumor in cancer patients and is involved in the organization of early phase clinical trials of therapeutic vaccination with antigenic peptides, such as tyrosinase, in advanced melanoma patients. The collaboration funded by this FNS grant aims at determining the exact role of ERAD in the generation of tyrosinase-derived tumor antigen. The results from this research project will have implications for the understanding of basic mechanisms of antigen processing and presentation to T cells. They will also provide valuable clues to enhance the efficacy of peptide-based cancer vaccines.