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Published on: July 17, 2020
PTPN3 expressed in activated T lymphocytes is a candidate for a non-antibody-type immune checkpoint inhibitor
Akiko Fujimura1, Kazunori Nakayama1, Akira Imaizumi1
1Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
Abstract:
It has been shown that protein tyrosine phosphatase non-receptor type (PTPN) 3 inhibits T-cell activation. However, there is no definitive conclusion about how the inhibition of PTPN3 in lymphocytes affects immune functions in human lymphocytes. In the present study, we showed that PTPN3 inhibition significantly contributes to the enhanced activation of activated human lymphocytes. The PTPN3 expression of lymphocytes was significantly increased through the activation process using IL-2 and anti-CD3 mAb. Interestingly, inhibiting the PTPN3 expression in activated lymphocytes significantly augmented the proliferation, migration, and cytotoxicity through the phosphorylation of zeta-chain-associated protein kinase 70 (ZAP-70), lymphocyte-specific protein tyrosine kinase (LCK), and extracellular signal-regulated kinases (ERK). Lymphocyte activation by PTPN3 inhibition was observed only in activated CD3+ T cells and not in NK cells or resting T cells. In therapy experiments using autologous tumors and lymphocytes, PTPN3 inhibition significantly augmented the number of tumor-infiltrated lymphocytes and the cytotoxicity of activated lymphocytes. Our results strongly imply that PTPN3 acts as an immune checkpoint in activated lymphocytes and that PTPN3 inhibitor may be a new non-antibody-type immune checkpoint inhibitor for cancer therapy.
Insights
Inhibiting protein tyrosine phosphatase (PTPN) 3 enhances human T-cell activation, proliferation, and cytotoxicity. This suggests PTPN3 acts as an immune checkpoint, offering potential for novel cancer therapies.
Area of Science:
- Immunology
- Molecular Biology
- Cell Biology
Background:
- Protein tyrosine phosphatase (PTPN) 3 is known to inhibit T-cell activation.
- The precise impact of PTPN3 inhibition on human lymphocyte immune functions remains unclear.
Purpose of the Study:
- To investigate the role of PTPN3 in human lymphocyte activation and immune function.
- To explore the therapeutic potential of PTPN3 inhibition in cancer treatment.
Main Methods:
- Human lymphocytes were activated using IL-2 and anti-CD3 mAb.
- PTPN3 expression was inhibited in activated lymphocytes.
- Lymphocyte proliferation, migration, and cytotoxicity were assessed.
- Phosphorylation of ZAP-70, LCK, and ERK was analyzed.
- Therapeutic efficacy was evaluated in preclinical cancer models.
Main Results:
- PTPN3 expression increased during lymphocyte activation.
- PTPN3 inhibition significantly enhanced lymphocyte proliferation, migration, and cytotoxicity.
- Enhanced activation was mediated by increased phosphorylation of ZAP-70, LCK, and ERK.
- PTPN3 inhibition specifically affected activated CD3+ T cells, not NK cells or resting T cells.
- In vivo, PTPN3 inhibition boosted tumor-infiltrating lymphocytes and cytotoxicity.
Conclusions:
- PTPN3 functions as an immune checkpoint in activated human lymphocytes.
- PTPN3 inhibition enhances anti-tumor immune responses.
- PTPN3 inhibitors represent a potential new class of non-antibody immune checkpoint inhibitors for cancer therapy.
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