Concomitant deletion of Ptpn6 and Ptpn11 in T cells fails to improve anticancer responses
Pedro Ventura, Milica Gakovic, Berenice A. Fischer, Laura Spinelli, Giorgia Rota, Shalini Pathak, Hanif Javanmard Khameneh, Alessandro Zenobi, Sarah Thomson, Walter Birchmeier, Doreen A. Cantrell, Greta Guarda
Abstract
Abstract 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.