SHP2 blockade enhances anti-tumor immunity via tumor cell intrinsic and extrinsic mechanisms
Ye Wang, Morvarid Mohseni, Angelo L. Grauel, Javier Estrada Diez, Wei Guan, Simon Liang, Jiyoung Choi, Minying Pu, Dongshu Chen, Tyler Laszewski, Stephanie Schwartz, Jane Gu, Leandra Mansur, Tyler Burks, Lauren K. Brodeur, Roberto Velazquez, Steve G. Kovats, Bhavesh Pant, Giri Buruzula, Emily Deng, Julie Chen, Farid Sari‐Sarraf, Christina Dornelas, Malini Varadarajan, Haiyan Yu, Chen Liu, Joanne Lim, Huai-Xiang Hao, Xiaomo Jiang, Anthony S. Malamas, Matthew J. LaMarche, Felipe C. Geyer, Margaret E. McLaughlin, Carlotta Costa, Joel P. Wagner, David A. Ruddy, Pushpa Jayaraman, Nathaniel D. Kirkpatrick, Pu Zhang, Oleg Iartchouk, Kimberly Aardalen, Viviana Cremasco, Glenn Dranoff, Jeffrey A. Engelman, Serena J. Silver, Hongyun Wang, William D. Hastings, Silvia Goldoni
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.