Poster Presentation 30th Lorne Cancer Conference 2018

Targeting Protein Tyrosine Phosphatases(PTPs) to enhance the T cells cancer immunotherapy (#149)

Xin Du , Tony Tiganis , Florian Wiede

Immunotherapy has emerged as an exciting treatment for cancer. As one of the most promising immunotherapy, adoptive T cell therapy (ACT) has been under intense investigation. Although ACT has shown remarkable clinical efficacy in hematological malignancies, its success in combating solid tumours has been limited. Protein tyrosine phosphatases (PTPs) serve critical roles in the regulationg of lymphocyte activation to ensure sufficient immunity to pathogens and prevent autoimmunity. In some cases, PTPs inhibit lymphocyte activation, whereas in others they promote it. Protein tyrosine phosphatase N2 (PTPN2) negatively regulates αβ TCR signalling by dephosphorylating the most proximal tyrosine kinase in the TCR signalling casacade, the Src family kinase LCK. PTPN2 also antagonises cytokine signalling required for T cell function and homeostasis by dephosphorylating and inactivating Janus-activated kinase (JAK)-1 and JAK-3 and their target substrates signal transducer and activator of transcription (STAT)-1, STAT-3 and STAT-5 in a cell context-dependent manner. PTPN2 sets the threshold for productive TCR signalling and prevents overt responses to self-antigen in the context of T cell homeostasis and antigen cross-presentation to establish peripheral T cell tolerance. The importance of PTPN2 in immune tolerance is highlighted by the development of autoimmunity in aged T cell-specific PTPN2-deficient mice and the systemic inflammation and autoimmunity evident when PTPN2 is deleted in the hematopoietic compartment in adult mice.PTPN22 is a cytoplasmic PTPase expressed exclusively in hematopoietic cells and associates with Csk (C-terminal Src ty- rosine kinase) to inhibit TCR signaling through dephosphorylation of the autophosphoryla- tion site (Tyr394) of the Lck protein tyrosine, it has most impact on the development of effector/memory T cells. Here, we use PTPN2 knock mice as well as PTPN22 knock out mice to develope CAR-T cells to examine its enhancement of T cell specific killing of tumor cells. Further more we apply Cripr Cas9 to knock out PTPN2 and PTPN22 in normal T cells in order to make it more possible to be developed into clinical treatment in the future.