Poster Presentation 30th Lorne Cancer Conference 2018

PTPN2-deficiency enhances T cell mediated anti-tumour immunity (#281)

Florian Wiede 1 2 , Kun-Hui Lu 1 2 , Tony Tiganis 1 2
  1. Peter MacCallum Cancer Center, Melbourne, Victoria, Australia
  2. Biochemistry & Molecular Biology, Monash University, Clayton, Victoria, Australia

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. Our recent studies have identified protein tyrosine phosphatase N2 (PTPN2) as a key regulator of T cell receptor signaling serving to tune CD8+ T cells and prevent excessive responses to self in the context of T cell homeostasis1,2. We have shown that PTPN2-deficiency in CD8+ T cells permits the helper-independent acquisition of cytotoxic activity to neo-antigens3. These studies have established PTPN2’s critical role in antigen cross-presentation and the establishment of T cell tolerance.  Here we show that T cell-specific deletion of PTPN2 in T cells enhances tumour immunosurveillance and the efficacy of adoptively transferred tumour-specific T cells to both prevent and eradicate tumours. PTPN2-deficiency in T cells prevented tumour formation in aged mice heterozygous for the tumour suppressor p53. PTPN2-deficient adoptively transferred naïve CD8+ T cells alone markedly repressed tumour formation in a syngeneic murine model of triple negative breast cancer. The repression of tumour growth was accompanied by increased tumour CD8+ T cell infiltration and decreased CD8+ T cell exhaustion. These findings point towards a novel approach for enhancing the efficacy of ACT in otherwise recalcitrant solid tumours.

 

  1. Wiede F, Shields BJ, Chew SH, Kyparissoudis K, van Vliet CJ, Galic S, Tremblay ML, Russell SM, Godfrey DI, Tiganis T. T-cell protein tyrosine phosphatase attenuates T cell signaling for the maintenance of tolerance in mice. J. Clin. Invest. 2011 Dec 121(12):4758-74.
  2. Wiede F, La Gruta NL, Tiganis, T. PTPN2 attenuates T cell lymphopoenia-induced proliferation. Nat. Commun. 2014;5:3073. doi: 10.1038/ncomms4073.
  3. Wiede F, Ziegler A, Zehn D, Tiganis T. PTPN2 restrains CD8⁺ T cell responses after antigen cross-presentation for the maintenance of peripheral tolerance in mice. J Autoimmun. 2014 Sep;53:105-14.