SHP2 blockade enhances anti-tumor immunity via tumor cell intrinsic and extrinsic mechanisms
Open accessAbstract
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.
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SHP2 mediates signaling through PD-1 in T cells, and the PD-1/SHP2 axis mediates PD-1's immune suppressive effect.
“SHP2 mediates signaling through the immune checkpoint receptor PD-1 in T cells (49). As the PD-1/SHP2 signaling axis mediates the immune suppressive effect of PD-1”
From Expanding the Reach of Precision Oncology by Drugging All <i>KRAS</i> Mutants (2022) · cites this paper as [49]
SHP2 inhibition increased PD-L1 and MHC-I expression by augmenting intrinsic IFN-γ in cancer cells.
“SHP2 inhibition increased PD-L1 and MHC-I expression by augmenting intrinsic IFN-γ in cancer cells [252].”
From Combination strategies with PD-1/PD-L1 blockade: current advances and future directions (2022) · cites this paper as [252]
SHP2 inhibitor enhanced the efficacy of α-PD-1 in murine tumor models.
“SHP2 inhibitor enhanced the efficacy of α-PD-1 in murine tumor models [252–254].”
From Combination strategies with PD-1/PD-L1 blockade: current advances and future directions (2022) · cites this paper as [252]
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Allosteric inhibition of SHP2 rescues functional T-cell abnormalities in SAP deficiency
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MEST promotes immune escape in gastric cancer by downregulating MHCI expression via SHP2
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Molecular Mechanisms Driving Metastatic Progression Within the Aged Tumor Microenvironment
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Ten Years of CRISPRing Cancers In Vitro
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SHP2 inhibition improves celastrol-induced growth suppression of colorectal cancer
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High expression of SHP2 predicts a promising prognosis in colorectal cancer
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- Authors
- Wang, Y., Mohseni, M., Grauel, A., Diez, J. E., Guan, W., Liang, S., Choi, J. E., Pu, M., Chen, D., Laszewski, T., Schwartz, S., Gu, J., Mansur, L., Burks, T., Brodeur, L., Velazquez, R., Kovats, S., Pant, B., Buruzula, G., Deng, E., Chen, J. T., Sari-Sarraf, F., Dornelas, C., Varadarajan, M., Yu, H., Liu, C., Lim, J., Hao, H.-X., Jiang, X., Malamas, A., LaMarche, M. J., Geyer, F. C., McLaughlin, M., Costa, C., Wagner, J., Ruddy, D., Jayaraman, P., Kirkpatrick, N. D., Zhang, P., Iartchouk, O., Aardalen, K., Cremasco, V., Dranoff, G., Engelman, J. A., Silver, S., Wang, H., Hastings, W. D., & Goldoni, S.
- Affiliations
- Novartis Institutes for BioMedical Research (CH)
- Corresponding author
- Hastings, William D.
- Goldoni, Silvia
- ORCID
- Wang, Ye
- Mohseni, Morvarid
- Grauel, Angelo
- Liang, Simon
- Laszewski, Tyler
- Mansur, Leandra
- Burks, Tyler
- Velazquez, Roberto
- Pant, Bhavesh
- Chen, Julie T.
- Varadarajan, Malini
- Yu, Haiyan
- Liu, Chen
- Hao, Huai-Xiang
- Jiang, Xiaomo
- LaMarche, Matthew J.
- Geyer, Felipe Correa
- Costa, Carlotta
- Wagner, Joel
- Ruddy, David
- Zhang, Pu
- Iartchouk, Oleg
- Cremasco, Viviana
- Dranoff, Glenn
- Engelman, Jeffrey A.
- Silver, Serena
- Wang, Hongyun
- Goldoni, Silvia
- Venue
- Scientific Reports
- Published
- 2021-01-14
- Volume
- 11
- Issue
- 1
- Pages
- 1399-1399
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC7809281
- OpenAlex
- W3123801310
- Cited by
- 73
- References
- 60
- Citations by year
- 2026: 2 · 2025: 16 · 2024: 17 · 2023: 17 · 2022: 18 · 2021: 3
- FWCI
- 4.31
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Novartis Institutes for BioMedical Research
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- SHP2, protein tyrosine phosphatase, allosteric inhibitors, antitumor immunity, cancer immunotherapy, T cell cytotoxicity, interferon-gamma signaling, PD-L1, MHC class I, tumor microenvironment, myeloid cells, anti-PD-1 therapy, tumor cell-intrinsic signaling
- MeSH terms
- Animals, Humans, Immunity, Cellular, Mice, Inbred BALB C, Neoplasm Proteins, Neoplasms, Experimental, T-Lymphocytes, Signal Transduction, Cell Line, Tumor, Mice, Protein Tyrosine Phosphatase, Non-Receptor Type 11, Gene Knockout Techniques, HEK293 Cells
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