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


  • P.M.O. Ventura
  • M. Gakovic
  • B.A. Fischer
  • L. Spinelli
  • G. Rota
  • S. Pathak
  • H.J. Khameneh
  • A. Zenobi
  • S. Thomson
  • W. Birchmeier
  • D.A. Cantrell
  • G. Guarda


  • EMBO Reports


  • EMBO Rep 23 (11): e55399


  • Anticancer T cells acquire a dysfunctional state characterized by poor effector function and expression of inhibitory receptors, such as PD-1. Blockade of PD-1 leads to T cell reinvigoration and is increasingly applied as an effective anticancer treatment. Recent work challenged the commonly held view that the phosphatase PTPN11 (known as SHP-2) is essential for PD-1 signaling in T cells, suggesting functional redundancy with the homologous phosphatase PTPN6 (SHP-1). Therefore, we investigated the effect of concomitant Ptpn6 and Ptpn11 deletion in T cells on their ability to mount antitumour responses. In vivo data show that neither sustained nor acute Ptpn6/11 deletion improves T cell-mediated tumor control. Sustained loss of Ptpn6/11 also impairs the therapeutic effects of anti-PD1 treatment. In vitro results show that Ptpn6/11-deleted CD8(+) T cells exhibit impaired expansion due to a survival defect and proteomics analyses reveal substantial alterations, including in apoptosis-related pathways. These data indicate that concomitant ablation of Ptpn6/11 in polyclonal T cells fails to improve their anticancer properties, implying that caution shall be taken when considering their inhibition for immunotherapeutic approaches.