SHP2 blockade enhances anti-tumor immunity via tumor cell intrinsic and extrinsic mechanisms

Abstract

SHP2 is a ubiquitous tyrosine phosphatase involved in regulating both tumor and immune cell signaling. In this study, we discovered a novel immune modulatory function of SHP2. Targeting this protein with allosteric SHP2 inhibitors promoted anti-tumor immunity, including enhancing T cell cytotoxic function and immune-mediated tumor regression. Knockout of SHP2 using CRISPR/Cas9 gene editing showed that targeting SHP2 in cancer cells contributes to this immune response. Inhibition of SHP2 activity augmented tumor intrinsic IFNγ signaling resulting in enhanced chemoattractant cytokine release and cytotoxic T cell recruitment, as well as increased expression of MHC Class I and PD-L1 on the cancer cell surface. Furthermore, SHP2 inhibition diminished the differentiation and inhibitory function of immune suppressive myeloid cells in the tumor microenvironment. SHP2 inhibition enhanced responses to anti-PD-1 blockade in syngeneic mouse models. Overall, our study reveals novel functions of SHP2 in tumor immunity and proposes that targeting SHP2 is a promising strategy for cancer immunotherapy.

Combined Inhibition of SHP2 and CXCR1/2 Promotes Antitumor T-cell Response in NSCLC

“…Others have reported that SHP2is evoke meaningful anti-tumor T cell responses (5,6). These studies analyzed subcutaneous syngeneic tumors, which lack tissue-specific immunity and display mutational spectra that do not reflect the cognate human malignancies.…”

“…"Driver" mutations (e.g., amplified or mutant RTKs, mutant KRAS) significantly-and differentially-also have tumor cell-intrinsic and -extrinsic effects and evoke distinct cellular and humoral responses in different tissues (3). Consequently, SHP2is likely have important, potentially driver-specific, effects on the tumor microenvironment (TME), including potentially complex effects on anti-tumor immunity (2,(4)(5)(6).…”

SHP-2 and canonical PD-1: SHP-2 axis regulate myeloid cell differentiation, anti-tumor responses and innate immune memory

“…Other investigators reported that SHP-2 ablation in macrophages potentiated production of CXCL9 in response to IFN-, thereby facilitating tumor infiltration by T cells 110 . Combined approaches of SHP-2 allosteric inhibitors together with pharmacologic RTK inhibitors or KRAS G12C -GDP inhibitors have been employed with the main purpose of targeting signaling vulnerabilities of cancer 108,111,112 . These studies have reported that such treatments, by changing the properties of cancer, also alter immune cells of the TME, including increase of CD8 + T cells, depletion of pro-tumorigenic M2 TAMs via attenuation of Csf1 signaling 109 , increase of M1 TAMs and reduced immunosuppression function of MDSCs 107,108,112 , but the mechanisms remained elusive.…”

“…Combined approaches of SHP-2 allosteric inhibitors together with pharmacologic RTK inhibitors or KRAS G12C -GDP inhibitors have been employed with the main purpose of targeting signaling vulnerabilities of cancer 108,111,112 . These studies have reported that such treatments, by changing the properties of cancer, also alter immune cells of the TME, including increase of CD8 + T cells, depletion of pro-tumorigenic M2 TAMs via attenuation of Csf1 signaling 109 , increase of M1 TAMs and reduced immunosuppression function of MDSCs 107,108,112 , but the mechanisms remained elusive. Our present studies employing a genetic approach to dissect the effects of SHP-2 targeting at multiple levels, showed that myeloid-intrinsic but not T cell-intrinsic depletion of SHP-2 has a dominant anti-tumor effect by altering the myeloid lineage fate, thereby promoting the generation of differentiated granulocytes, and monocytes that became TAMs with signatures of activated antigen presenting cells.…”

“…Previous studies used allosteric inhibitors of SHP-2 such as SHP099, TNO155 106-108 and RMC4550 109 with the purpose to target cancer cells, in which SHP-2 is activated downstream of RTK/Ras signaling and functions as an oncogene promoting cancer cell growth 106 , or to target both cancer and immune cells 108,109 . These studies observed upregulation of three CXCR3 ligands, specifically CXCL9, 22 CXCL10, CXCL11 in tumor cells thereby leading to T cell recruitment 108 . Other investigators reported that SHP-2 ablation in macrophages potentiated production of CXCL9 in response to IFN-, thereby facilitating tumor infiltration by T cells 110 .…”