Allosteric inhibition of SHP2 stimulates anti-tumor immunity by transforming the immunosuppressive environment.

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 anti-tumor 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. Additionally, RMC-4550 drove direct, selective depletion of pro-tumorigenic M2 macrophages via attenuation of CSF-1 receptor signaling and increased M1 macrophages via a mechanism independent of CD8+T-cells or IFN-γ. These dramatic shifts in polarized macrophage populations in favor of anti-tumor immunity were not seen with checkpoint blockade. Consistent with a pleiotropic mechanism of action, RMC-4550 in combination with either checkpoint or CSF-1R blockade caused additive anti-tumor 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 anti-tumor immune responses. Furthermore, these data suggest that inhibition of SHP2 is a promising investigational therapeutic approach.