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

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

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

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Item Type:	Article
Title:	Concomitant deletion of Ptpn6 and Ptpn11 in T cells fails to improve anticancer responses
Creators Name:	Ventura, P.M.O., Gakovic, M., Fischer, B.A., Spinelli, L., Rota, G., Pathak, S., Khameneh, H.J., Zenobi, A., Thomson, S., Birchmeier, W., Cantrell, D.A. and Guarda, G.
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.
Keywords:	PD-1 Checkpoint Blockade, Ptpn11, Ptpn6, T Cell Exhaustion, Animals, Mice
Source:	EMBO Reports
ISSN:	1469-221X
Publisher:	EMBO Press / Wiley
Volume:	23
Number:	11
Page Range:	e55399
Date:	7 November 2022
Official Publication:	https://doi.org/10.15252/embr.202255399
PubMed:	View item in PubMed

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