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Updated: Aug 26, 2025

Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors
08:45

Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors

Published on: July 17, 2020

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Concomitant deletion of Ptpn6 and Ptpn11 in T cells fails to improve anticancer responses

Pedro M O Ventura1, Milica Gakovic2, Berenice A Fischer1

  • 1Institute for Research in Biomedicine, Università della Svizzera Italiana, Bellinzona, Switzerland.

EMBO Reports
|October 4, 2022
PubMed

Insights

Deleting phosphatases PTPN6 (SHP-1) and PTPN11 (SHP-2) together in T cells does not enhance anticancer immunity. This combined deletion also hinders anti-PD-1 therapy effectiveness, suggesting caution for immunotherapeutic strategies.

Area of Science:

  • Immunology
  • Cancer Biology
  • Molecular Biology

Background:

  • Anticancer T cells can become dysfunctional, expressing inhibitory receptors like PD-1.
  • Blocking PD-1 reinvigorates T cells and is a key anticancer treatment.
  • The roles of phosphatases PTPN6 (SHP-1) and PTPN11 (SHP-2) in PD-1 signaling are debated, with potential functional redundancy.

Purpose of the Study:

  • To investigate the impact of simultaneously deleting Ptpn6 and Ptpn11 in T cells on antitumor responses.
  • To determine if combined Ptpn6/11 deletion enhances T cell-mediated tumor control or anti-PD-1 therapy efficacy.

Main Methods:

  • In vivo studies of T cell-mediated tumor control following Ptpn6/11 deletion.
  • Assessment of anti-PD-1 treatment efficacy in Ptpn6/11-deleted T cells.
  • In vitro analysis of Ptpn6/11-deleted CD8+ T cell expansion and survival.
  • Proteomics analysis to identify molecular alterations in deleted T cells.

Main Results:

  • Neither sustained nor acute deletion of Ptpn6/11 improved T cell-mediated tumor control in vivo.
  • Sustained loss of Ptpn6/11 impaired the therapeutic benefits of anti-PD-1 treatment.
  • Ptpn6/11-deleted CD8+ T cells showed reduced expansion due to impaired survival.
  • Proteomics revealed significant changes in apoptosis-related pathways in deleted T cells.

Conclusions:

  • Concomitant deletion of Ptpn6 and Ptpn11 in T cells does not enhance their anticancer properties.
  • Inhibition of both PTPN6 and PTPN11 may be detrimental to T cell function and immunotherapy.
  • Caution is advised when considering the inhibition of these phosphatases for cancer immunotherapy.
Keywords:
PD-1 checkpoint blockadePtpn11Ptpn6T cell exhaustion

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