PTPN2/1
OVERVIEW
Protein tyrosine phosphatase non-receptor type 2 and protein tyrosine phosphatase non-receptor type 2 (PTPN2/1) are closely related members of the protein tyrosine phosphatase family.1 PTPN2/1 is a negative regulator of multiple signaling pathways including cytokine signaling in immune cells.2,3 Targets of PTPN2 include cytokine receptors, T-cell receptor (TCR) family members, SRC family members, and JAK/STAT family members.1 The role of PTPN2 in immune cells is exemplified by the fact that PTPN2 knockout mice have severe systemic inflammatory disease.4
Adapted from Shuai K, et al. 2003
IMPLICATIONS IN CANCER
PTPN2/1 inhibition drives both tumor cell dependent and immune cell dependent anti-cancer mechanisms of action.5 Loss of PTPN2/1 in tumor cells enhances sensitivity to immune checkpoint inhibitors by maintaining active phosphate signaling pathways. PTPN2/N1 inhibition in tumor cells promotes IFN signaling through the JAK/STAT pathway resulting in growth delay, increased tumor antigen presentation, and elevated pro-inflammatory chemokine release.6 Additionally, PTPN2/N1 inhibition promotes the activation and proinflammatory anti-tumorigenic function of multiple immune cell subsets. In T cells, PTPN2/N1 act as a negative regulators of TCR signaling whereby inhibition of these enzymes results in T cell activation, proliferation and immune effector functions, including tumoricidal action.7
Related Research
- Ibarra-Sanchez MJ, et al. The T-cell protein tyrosine phosphatase. Semin Immunol. 2000;12:379-386.
- LaFleur MW, et al. PTPN2 regulates the generation of exhausted CD8+ T cell subpopulations and restrains tumor immunity. Nat Immunol. 2019;20(10):1335-1347.
- Shuai K, et al. Regulation of JAK-STAT signalling in the immune system. Nat Rev Immunol. 2003;(3)900-911.
- Heinonen KM, et al. T-cell protein tyrosine phosphatase deletion results in progressive systemic inflammatory disease. Blood. 2004;103(9):3457-3464.
- Manguso RT, et al. In vivo CRISPR screening identifies Ptpn2 as a cancer immunotherapy target. Nature. 2017;547(7664):413-418.
- Baumgartner CK, et al. ABBV-CLS-484: An active site PTPN2/N1 inhibitor that augments the immune response and sensitizes tumors to immune-mediated killing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr ND06.
- Wiede, F. et al. T cell protein tyrosine phosphatase attenuates T cell signaling to maintain tolerance in mice. J Clin Invest. 2011;121:4758-4774.
