|M.Sc Student||Dvir Sagie|
|Subject||The Effect of Epigenome Modulation on the HLA Peptidome|
|Department||Department of Biology||Supervisor||Professor Arie Admon|
|Full Thesis text|
Cancer is the second leading cause of death globally, estimated to account for 9.6 million deaths in 2018 worldwide. The conventional approaches to cancer treatment include in many cases surgery to remove the growth, followed by radiation and chemotherapy. Another approach that has shown successful results in treating several types of cancer in recent years is immunotherapy. This approach is based on the ability of the immune system to detect "non-self" proteins that are specifically expressed in tumor cells and eliminate those cells. Such proteins include cancer testis antigens (CTAs), which are ideal candidates for immunotherapy since they are present only in immune privileged sites in the adult body, thus an autoimmune response is prevented. The peptides generated from these proteins can be presented on the HLA molecules at the surface of the tumor cells leading to efficient immune response specifically against cancerous cells. The main objective of this research was to examine the effects of epigenetic modulator drugs on the HLA peptidome in an attempt to discover HLA peptides suitable for use as a cancer vaccine. It is possible to purify the HLA molecules with their bound peptide using biochemical methods such as immunoaffinity. This way we are able to identify the unique peptides that were generated as a result of the drug treatments.
The pattern of genetic alternations in cancer cells is diverse and varies between different types of cancer and patients. Therefore, the identification of peptides from the patient’s tumor can contribute to a personalized treatment according to the mutations in the patient, which will increase the success of the treatment. In this study, the epigenetic modulator drugs were decitabine (DNA methyltransferase inhibitor) and vorinostat (Histone deacetylase inhibitor). Both of the drugs display cytotoxic effects besides their epigenetic ones and are already used in the clinic for treating different types of cancer, such as acute myeloid leukemia and cutaneous T cell lymphoma. After treating different cultured leukemia cell lines with decitabine, vorinostat or both of the drugs, the proteins and HLA peptides were purified and analyzed using a mass spectrometer. Most of the proteins and HLA peptide were not significantly affected by the drug treatments. However, a specific group of HLA peptides was identified only after the different treatments and not in the control samples. A number of these peptides are known as CTAs and have the potential to activate the immune system. These findings could present a new methodology to treat cancer and combines epigenetic modulation with personalized immunotherapy, thus improving the overall success rate of the treatments against cancer.