The protein-tyrosine phosphatase SHP2 promotes oncogenic RAS/MAPK pathway activation in different tumor types. In immune cells, SHP2 binds to phosphorylated ITIM and ITAM domains on regulatory receptors, including PD-1. We have shown that RMC-4550, a SHP2 allosteric inhibitor, attenuates tumor growth in syngeneic mouse tumor models with effects equivalent to, or greater than those of checkpoint inhibitors. Consistent with anti-tumor immunity as the mechanism, tumor growth inhibition (TGI) was not observed in immunocompromised mice. TGI was associated with changes in the tumor immune microenvironment, in both the adaptive and innate arms. Similar to checkpoint blockade, the frequency of CD8+T cell infiltrates was increased upon treatment with RMC-4550. Polarized macrophage populations were significantly shifted in favor of antitumor immunity, with marked increases in M1 and decreases in M2 cells, effects not seen with checkpoint blockade. The objective of the present study was to determine if the effect on tumor-associated macrophage (TAM) polarization is secondary to a release of the biochemical brakes on adaptive immunity and/or a result of a direct effect of SHP2 on TAMs.

In vivo administration of RMC-4550 in the CT26 syngeneic model significantly decreased M2, and increased M1, TAM after CD8+T cell depletion or IFNγ blockade, similar to the response in control animals. In vitro, SHP2 inhibition attenuated CSF1R signaling in murine bone marrow-derived macrophages and selectively induced apoptotic cell death in M2, but not M1, polarized macrophages. In addition, RMC-4550 treatment in vitro reduced the suppressive potential of human M-MDSCs. Collectively these observations suggest that SHP2 inhibition directly impacts the survival and function of suppressive monocytic immune cells. Given the effect of SHP2 inhibition on the CSF1R signaling pathway, we assessed whether the anti-tumor activity of RMC-4550 was similar to that of CSF1R blockade. In contrast to RMC-4550, anti-CSF1R antibody did not induce a significant delay in CT26 tumor growth. These results confirm that RMC-4550 has pleiotropic effects on the immune system including modulation of both adaptive and innate mechanisms. In summary, we propose that SHP2 plays a central role in inducing immune suppression in the tumor microenvironment by both inhibiting T cells and supporting the viability of pro-tumorigenic macrophages. Thus, SHP2 inhibition represents a novel investigational strategy with dual activity: direct inhibition of cancer cell growth in certain tumors as well as promotion of an anti-tumor immune response by direct transformation of the tumor immune microenvironment. Tumors that are intrinsically dependent upon SHP2 and exhibit a myeloid-rich microenvironment could be particularly susceptible to this dual-mechanism therapeutic strategy.

Citation Format: Elsa Quintana, Chris J. Schulze, Tiffany J. Choy, Darienne R. Myers, Kasia Mordec, Dylan Daniel, Mark A. Goldsmith, Jan A. Smith. Allosteric inhibition of SHP2 suppresses CSF1R signaling and selectively reduces viability of M2 tumor associated macrophages contributing to anti-tumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5019.