2019
DOI: 10.1016/j.apsb.2018.08.009
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SHP2 inhibition triggers anti-tumor immunity and synergizes with PD-1 blockade

Abstract: Tyrosine phosphatase SHP2 is a promising drug target in cancer immunotherapy due to its bidirectional role in both tumor growth promotion and T-cell inactivation. Its allosteric inhibitor SHP099 is known to inhibit cancer cell growth both in vitro and in vivo . However, whether SHP099-mediated SHP2 inhibition retards tumor growth in vivo via anti-tumor immunity remains elusive. To address this, a CT-26 colon cancer xenograft model was establi… Show more

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Cited by 152 publications
(129 citation statements)
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“…It is conceivable that the mechanism of regulation of SHP2 activity described here applies generally to SHP2 activation by bidentate phosphopeptides in multiple contexts, albeit with different structural and biophysical parameters. In the case of the SHP2-PD-1 interaction, we believe that the interface between the N-SH2 and C-SH2 domains, which is formed upon full activation and holds SHP2 in the open active conformation, represents a potential target to affect SHP2 activation selectively in the context of PD-1 signaling (35). Preventing the formation of this interface would decrease, but not abolish, PD-1 signaling.…”
Section: Discussionmentioning
confidence: 99%
“…It is conceivable that the mechanism of regulation of SHP2 activity described here applies generally to SHP2 activation by bidentate phosphopeptides in multiple contexts, albeit with different structural and biophysical parameters. In the case of the SHP2-PD-1 interaction, we believe that the interface between the N-SH2 and C-SH2 domains, which is formed upon full activation and holds SHP2 in the open active conformation, represents a potential target to affect SHP2 activation selectively in the context of PD-1 signaling (35). Preventing the formation of this interface would decrease, but not abolish, PD-1 signaling.…”
Section: Discussionmentioning
confidence: 99%
“…Phosphatases, such as SHP1, SHP2, DUSP2 [2], and CD45 [141], have also been implicated in the negative regulation of JAK-STAT signaling through their dephosphorylation of tyrosine residues on JAKs, STATs, and kinase-bound receptors, such as IFNAR [129], to facilitate rapid reactivation. Unsurprisingly, SHP2, which negatively regulates STAT1 and is heavily linked to T cell regulation, has been found to synergistically work with anti-PD1 to promote short-term antitumor immune responses when inhibited [142]. On the other hand, SHP1 has been found to act as a tumor suppressor in liver cancer by deactivating STAT3 and subsequent errant NFκB signaling [143].…”
Section: Stat Signaling: Interactions and Inhibitionmentioning
confidence: 99%
“…In addition, immunogenic cancers developed in these mice with kinetics similar to the ones observed in the control groups (156). Along these lines, studies by others showed that the growth of immunogenic tumors in mice lacking Shp-2 in T cells was moderately retarded or accelerated, but even in the former case the effects on tumor growth were distant from the ones of PD-1-deficiency (154,160,161). One interpretation is that the therapeutic effects of PD-1 blockade are not largely mediated by T cells, a quite unlikely hypothesis in light of cytotoxic T cell depletion results (131,162).…”
Section: Shp-2 and Inhibitory Receptor Signaling In T And Nk Cellsmentioning
confidence: 57%
“…With respect to this question, conditional PD-1 deletion will be informative. Most importantly, genetic deletion or pharmacological inhibition of Shp-2 did not prevent the therapeutic benefit of antibody-mediated PD-1 blockade (156,161). These results challenge the possibility that IRs antagonize TCR and co-stimulatory signaling by reducing the availability of this phosphatase and imply that PD-1 signaling occurs in the absence of Shp-2 activity.…”
Section: Shp-2 and Inhibitory Receptor Signaling In T And Nk Cellsmentioning
confidence: 90%