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 cyt...

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Autores principales:	Ye Wang, Morvarid Mohseni, Angelo Grauel, Javier Estrada Diez, Wei Guan, Simon Liang, Jiyoung Elizabeth Choi, Minying Pu, Dongshu Chen, Tyler Laszewski, Stephanie Schwartz, Jane Gu, Leandra Mansur, Tyler Burks, Lauren Brodeur, Roberto Velazquez, Steve Kovats, Bhavesh Pant, Giri Buruzula, Emily Deng, Julie T. Chen, Farid Sari-Sarraf, Christina Dornelas, Malini Varadarajan, Haiyan Yu, Chen Liu, Joanne Lim, Huai-Xiang Hao, Xiaomo Jiang, Anthony Malamas, Matthew J. LaMarche, Felipe Correa Geyer, Margaret McLaughlin, Carlotta Costa, Joel Wagner, David Ruddy, Pushpa Jayaraman, Nathaniel D. Kirkpatrick, Pu Zhang, Oleg Iartchouk, Kimberly Aardalen, Viviana Cremasco, Glenn Dranoff, Jeffrey A. Engelman, Serena Silver, Hongyun Wang, William D. Hastings, Silvia Goldoni
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/aeca1d5b6b344aeabcc21b726ae4f617
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spelling	oai:doaj.org-article:aeca1d5b6b344aeabcc21b726ae4f6172021-12-02T14:01:22ZSHP2 blockade enhances anti-tumor immunity via tumor cell intrinsic and extrinsic mechanisms10.1038/s41598-021-80999-x2045-2322https://doaj.org/article/aeca1d5b6b344aeabcc21b726ae4f6172021-01-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-80999-xhttps://doaj.org/toc/2045-2322Abstract 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.Ye WangMorvarid MohseniAngelo GrauelJavier Estrada DiezWei GuanSimon LiangJiyoung Elizabeth ChoiMinying PuDongshu ChenTyler LaszewskiStephanie SchwartzJane GuLeandra MansurTyler BurksLauren BrodeurRoberto VelazquezSteve KovatsBhavesh PantGiri BuruzulaEmily DengJulie T. ChenFarid Sari-SarrafChristina DornelasMalini VaradarajanHaiyan YuChen LiuJoanne LimHuai-Xiang HaoXiaomo JiangAnthony MalamasMatthew J. LaMarcheFelipe Correa GeyerMargaret McLaughlinCarlotta CostaJoel WagnerDavid RuddyPushpa JayaramanNathaniel D. KirkpatrickPu ZhangOleg IartchoukKimberly AardalenViviana CremascoGlenn DranoffJeffrey A. EngelmanSerena SilverHongyun WangWilliam D. HastingsSilvia GoldoniNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-23 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Ye Wang Morvarid Mohseni Angelo Grauel Javier Estrada Diez Wei Guan Simon Liang Jiyoung Elizabeth Choi Minying Pu Dongshu Chen Tyler Laszewski Stephanie Schwartz Jane Gu Leandra Mansur Tyler Burks Lauren Brodeur Roberto Velazquez Steve Kovats Bhavesh Pant Giri Buruzula Emily Deng Julie T. Chen Farid Sari-Sarraf Christina Dornelas Malini Varadarajan Haiyan Yu Chen Liu Joanne Lim Huai-Xiang Hao Xiaomo Jiang Anthony Malamas Matthew J. LaMarche Felipe Correa Geyer Margaret McLaughlin Carlotta Costa Joel Wagner David Ruddy Pushpa Jayaraman Nathaniel D. Kirkpatrick Pu Zhang Oleg Iartchouk Kimberly Aardalen Viviana Cremasco Glenn Dranoff Jeffrey A. Engelman Serena Silver Hongyun Wang William D. Hastings Silvia Goldoni SHP2 blockade enhances anti-tumor immunity via tumor cell intrinsic and extrinsic mechanisms
description	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.
format	article
author	Ye Wang Morvarid Mohseni Angelo Grauel Javier Estrada Diez Wei Guan Simon Liang Jiyoung Elizabeth Choi Minying Pu Dongshu Chen Tyler Laszewski Stephanie Schwartz Jane Gu Leandra Mansur Tyler Burks Lauren Brodeur Roberto Velazquez Steve Kovats Bhavesh Pant Giri Buruzula Emily Deng Julie T. Chen Farid Sari-Sarraf Christina Dornelas Malini Varadarajan Haiyan Yu Chen Liu Joanne Lim Huai-Xiang Hao Xiaomo Jiang Anthony Malamas Matthew J. LaMarche Felipe Correa Geyer Margaret McLaughlin Carlotta Costa Joel Wagner David Ruddy Pushpa Jayaraman Nathaniel D. Kirkpatrick Pu Zhang Oleg Iartchouk Kimberly Aardalen Viviana Cremasco Glenn Dranoff Jeffrey A. Engelman Serena Silver Hongyun Wang William D. Hastings Silvia Goldoni
author_facet	Ye Wang Morvarid Mohseni Angelo Grauel Javier Estrada Diez Wei Guan Simon Liang Jiyoung Elizabeth Choi Minying Pu Dongshu Chen Tyler Laszewski Stephanie Schwartz Jane Gu Leandra Mansur Tyler Burks Lauren Brodeur Roberto Velazquez Steve Kovats Bhavesh Pant Giri Buruzula Emily Deng Julie T. Chen Farid Sari-Sarraf Christina Dornelas Malini Varadarajan Haiyan Yu Chen Liu Joanne Lim Huai-Xiang Hao Xiaomo Jiang Anthony Malamas Matthew J. LaMarche Felipe Correa Geyer Margaret McLaughlin Carlotta Costa Joel Wagner David Ruddy Pushpa Jayaraman Nathaniel D. Kirkpatrick Pu Zhang Oleg Iartchouk Kimberly Aardalen Viviana Cremasco Glenn Dranoff Jeffrey A. Engelman Serena Silver Hongyun Wang William D. Hastings Silvia Goldoni
author_sort	Ye Wang
title	SHP2 blockade enhances anti-tumor immunity via tumor cell intrinsic and extrinsic mechanisms
title_short	SHP2 blockade enhances anti-tumor immunity via tumor cell intrinsic and extrinsic mechanisms
title_full	SHP2 blockade enhances anti-tumor immunity via tumor cell intrinsic and extrinsic mechanisms
title_fullStr	SHP2 blockade enhances anti-tumor immunity via tumor cell intrinsic and extrinsic mechanisms
title_full_unstemmed	SHP2 blockade enhances anti-tumor immunity via tumor cell intrinsic and extrinsic mechanisms
title_sort	shp2 blockade enhances anti-tumor immunity via tumor cell intrinsic and extrinsic mechanisms
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/aeca1d5b6b344aeabcc21b726ae4f617
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SHP2 blockade enhances anti-tumor immunity via tumor cell intrinsic and extrinsic mechanisms

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