Author:
Wang Ye,Mohseni Morvarid,Grauel Angelo,Diez Javier Estrada,Guan Wei,Liang Simon,Choi Jiyoung Elizabeth,Pu Minying,Chen Dongshu,Laszewski Tyler,Schwartz Stephanie,Gu Jane,Mansur Leandra,Burks Tyler,Brodeur Lauren,Velazquez Roberto,Kovats Steve,Pant Bhavesh,Buruzula Giri,Deng Emily,Chen Julie T.,Sari-Sarraf Farid,Dornelas Christina,Varadarajan Malini,Yu Haiyan,Liu Chen,Lim Joanne,Hao Huai-Xiang,Jiang Xiaomo,Malamas Anthony,LaMarche Matthew J.,Geyer Felipe Correa,McLaughlin Margaret,Costa Carlotta,Wagner Joel,Ruddy David,Jayaraman Pushpa,Kirkpatrick Nathaniel D.,Zhang Pu,Iartchouk Oleg,Aardalen Kimberly,Cremasco Viviana,Dranoff Glenn,Engelman Jeffrey A.,Silver Serena,Wang Hongyun,Hastings William D.,Goldoni Silvia
Abstract
AbstractSHP2 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.
Funder
Novartis Institutes for BioMedical Research
Publisher
Springer Science and Business Media LLC