PTPN2/N1
OVERVIEW
Protein tyrosine phosphatase non-receptor type 2 and protein tyrosine phosphatase non-receptor type 1 (PTPN2/N1) are closely related members of the protein tyrosine phosphatase family that act as negative regulators of multiple signaling pathways including cytokine signaling in immune cells.1,2 PTPN2 and PTPN1 target signaling molecules within the TCR and cytokine signaling pathways including SRC and JAK/STAT family members.1-3 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/N1 inhibition drives both tumor cell dependent and immune cell dependent anti-cancer mechanisms of action.5-11 Loss of PTPN2/N1 in tumor cells enhances sensitivity to immune checkpoint inhibitors by maintaining active phosphate signaling pathways.5 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 negative regulators of TCR and cytokine signaling; inhibition of these enzymes augments T cell activation, metabolism, proliferation and immune effector functions including tumoricidal action.3,6,9-11 Furthermore, pharmacologic PTPN2/N1 inhibition reduces T-cell exhaustion.6
Related Research
- Simoncic PD, et al. The T cell protein tyrosine phosphatase is a negative regulator of Janus family kinases 1 and 3. Curr Biol. 2002;12(6):446-53.
- Myers MP, et al. TYK2 and JAK2 are substrates of protein-tyrosine phosphatase 1B. J Biol Chem. 2001;276(51):47771-4.
- 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.
- 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. The PTPN2/PTPN1 inhibitor ABBV-CLS-484 unleashes potent anti-tumour immunity. Nature. 2023;622(7984):850-862.
- Penafuerte C, et al. Downregulation of PTP1B and TC-PTP phosphatases potentiate dendritic cell-based immunotherapy through IL-12/IFNγ signaling. Oncoimmunology. 2017;6(6):e1321185.
- Hering L et al. Protein tyrosine phosphatase non-receptor type 2 function in dendritic cells is crucial to maintain tissue tolerance. Front Immunol. 2020;11:1856.
- Flosbach M, et al. PTPN2 deficiency enhances programmed T cell expansion and survival capacity of activated T cells. Cell Rep. 2020;32:107957.
- Wiede F, et al. PTPN2 phosphatase deletion in T cells promotes anti-tumour immunity and CAR T-cell efficacy in solid tumours. EMBO J. 2020;39:e103637.
- Wiede, F. et al. PTP1B is an intracellular checkpoint that limits T-cell and CAR T-cell anti-tumor immunity. Cancer Discov. 2022;12, 752–773.
