Allosteric Inhibition of SHP2 Stimulates Antitumor Immunity by Transforming the Immunosuppressive Environment.

Autor:	Quintana E; Department of Biology, Revolution Medicines, Inc., Redwood City, California., Schulze CJ; Department of Biology, Revolution Medicines, Inc., Redwood City, California., Myers DR; Department of Biology, Revolution Medicines, Inc., Redwood City, California., Choy TJ; Department of Biology, Revolution Medicines, Inc., Redwood City, California., Mordec K; Department of Biology, Revolution Medicines, Inc., Redwood City, California., Wildes D; Department of Biology, Revolution Medicines, Inc., Redwood City, California., Shifrin NT; Department of Biology, Revolution Medicines, Inc., Redwood City, California., Belwafa A; Department of Biology, Revolution Medicines, Inc., Redwood City, California., Koltun ES; Department of Chemistry, Revolution Medicines, Inc., Redwood City, California., Gill AL; Department of Chemistry, Revolution Medicines, Inc., Redwood City, California., Singh M; Department of Biology, Revolution Medicines, Inc., Redwood City, California., Kelsey S; Department of Biology, Revolution Medicines, Inc., Redwood City, California.; Department of Chemistry, Revolution Medicines, Inc., Redwood City, California., Goldsmith MA; Department of Biology, Revolution Medicines, Inc., Redwood City, California.; Department of Chemistry, Revolution Medicines, Inc., Redwood City, California., Nichols R; Department of Biology, Revolution Medicines, Inc., Redwood City, California., Smith JAM; Department of Biology, Revolution Medicines, Inc., Redwood City, California. jan@revmed.com.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2020 Jul 01; Vol. 80 (13), pp. 2889-2902. Date of Electronic Publication: 2020 Apr 29.
DOI:	10.1158/0008-5472.CAN-19-3038
Abstrakt:	The protein tyrosine phosphatase SHP2 binds to phosphorylated signaling motifs on regulatory immunoreceptors including PD-1, but its functional role in tumor immunity is unclear. Using preclinical models, we show that RMC-4550, an allosteric inhibitor of SHP2, induces antitumor immunity, with effects equivalent to or greater than those resulting from checkpoint blockade. In the tumor microenvironment, inhibition of SHP2 modulated T-cell infiltrates similar to checkpoint blockade. In addition, RMC-4550 drove direct, selective depletion of protumorigenic M2 macrophages via attenuation of CSF1 receptor signaling and increased M1 macrophages via a mechanism independent of CD8 + T cells or IFNγ. These dramatic shifts in polarized macrophage populations in favor of antitumor immunity were not seen with checkpoint blockade. Consistent with a pleiotropic mechanism of action, RMC-4550 in combination with either checkpoint or CSF1R blockade caused additive antitumor activity with complete tumor regressions in some mice; tumors intrinsically sensitive to SHP2 inhibition or checkpoint blockade were particularly susceptible. Our preclinical findings demonstrate that SHP2 thus plays a multifaceted role in inducing immune suppression in the tumor microenvironment, through both targeted inhibition of RAS pathway-dependent tumor growth and liberation of antitumor immune responses. Furthermore, these data suggest that inhibition of SHP2 is a promising investigational therapeutic approach. SIGNIFICANCE: Inhibition of SHP2 causes direct and selective depletion of protumorigenic M2 macrophages and promotes antitumor immunity, highlighting an investigational therapeutic approach for some RAS pathway-driven cancers. (©2020 American Association for Cancer Research.)
Databáze:	MEDLINE
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