LABORATORIO DI PATOLOGIA GENERALE E IMMUNOLOGIA “GIOVANNA TOSI” - DMC - VARESE

Our research group focusses the investigation on two major areas: 1- the mechanisms controlling the adaptive immune response against the tumor; 2- the interaction between infectious retroviruses, particularly human oncogenic retroviruses, and host cells. We made the seminal discovery that the HLA class II genes, whose products present antigens to T helper cells triggering the immune response, are under the control of a molecule defined as MHC class II transactivator or CIITA. Moreover, recently we found that CIITA acts also as restriction factor for human retroviruses blocking their replication within the infected cell. Based on the above discoveries we are presently investigating: 1. Novel strategies of anti-tumor immunotherapy. These are based on the use of CIITA to make tumor cells HLA class II-positive and then render them antigen-presenting cells for their own tumor antigens. This strategy has been proven to trigger a potent immune response in vivo in the animal experimental model with consequent rejection of the tumor. We have applied this methodology to human tumor setting, in particular to hepatocarcinoma, to isolate tumor peptides directly from the HLA class II molecules and set up a multi-peptide vaccine. The project has been granted by the European Community and is presently in the phase of clinical trial (www.hepavac.eu). We now want to apply a similar protocol and strategy for creating an immunotherapeutic vaccine against the glioblastoma, the most frequent and serious tumor of the central nervous system, for which at present there is no effective therapy. Our strategy will be complemented by the use of oncolytic viruses, not only for their direct lytic activity on the tumor cells, but also for their effect on the liberation of large quantities of putative tumor antigens that will increase the triggering of the adaptive immune response generated by the glioma cells expressing CIITA. 2. Our recent discover that CIITA acts as restriction factor for HTLV-1 has opened the possibility to use CIITA to counteract not only the viral replication but also the potential of the virus to transform the host cell. We are therefore planning to investigate in detail the cellular and molecular mechanism at the basis of the oncogenicity of HTLV-1 and the strategies to implement the CIITA expression in infected cells before they undergo neoplastic transformation.