Oral Presentation The Melbourne Immunotherapy Network Winter Symposium 2019

Targeting PTPN2 to enhance T cell mediated anti-tumour immunity (#22)

Florian Wiede 1 2 3 , Kun-Hui Lu 3 , Xin Du 3 , Katharina Hochheiser 3 4 5 , Garron T Dodd 1 2 , Shuwei Liang 1 2 3 , Peih Goh 1 2 3 , Conor Kearney 3 , Deborah Meyran 3 , Paul A Beavis 3 6 , Melissa A Henderson 3 , Simone L Park 4 5 , Jason Waithman 7 , Sheng Zhang 8 , Zhong-Yin Zhang 8 , Jane Oliaro 3 6 , Thomas Gebhardt 5 6 , Phillip K Darcy 3 6 , Tony Tiganis 1 2 3
  1. Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia
  2. Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia
  3. Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
  4. Department of Microbiology and Immunology, University of Melbourne, Parkville, VIC, Australia
  5. Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia
  6. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia
  7. Telethon Kids Institute, University of Western Australia, Perth, Western Australia, Australia
  8. Department of Medicinal Chemistry and Molecular Pharmacology, Institute for Drug Discovery, Purdue University, West Lafayette, IN 47907-2084, USA

Adoptive T cell therapy (ACT) has emerged as an exciting approach for combating cancer. Although ACT has shown remarkable clinical efficacy in hematological malignancies, its success in combating solid tumours has been limited.  Here we report that PTPN2 deletion in T cells enhances cancer immunosurveillance and the efficacy of adoptively transferred tumour-specific T cells. PTPN2-deficient T cells markedly repressed tumour formation in mice bearing mammary tumours or melanomas. The repression of tumour growth was accompanied by increased tumour T cell infiltration and decreased T cell exhaustion. Moreover, PTPN2 deletion/knock-down/inhibition in T cells expressing a chimeric antigen receptor (CAR) specific for the oncoprotein HER2 increased CAR T-cell homing and activation and eradicated HER2-expressing syngeneic tumours in vivo, whereas PTPN2 inhibition increased the cytotoxic potential of human CAR T cells ex vivo. Our findings define PTPN2 as a target for bolstering T-cell mediated anti-tumour immunity and CAR T cell therapy and point towards a novel approach for enhancing the efficacy of ACT in otherwise recalcitrant solid tumours.