Cited by 195Protein Tyrosine PhosphatasesCancer Immunotherapy and BiomarkersImmunotherapy and Immune Responses

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SHP2 inhibition triggers anti-tumor immunity and synergizes with PD-1 blockade

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Zhao, Mingxia, Guo, Wenjie, Wu, Yuanyuan, Yang, Chenxi, Zhong, Liang, Deng, Guoliang, Zhu, Yuyu, Liu, Wen, Gu, Yanhong, Lu, Yin, Kong, Lingdong, Meng, Xiangbao, Xu, Qiang, Sun, Yang·2019·Acta Pharmaceutica Sinica B

DOI 10.1016/j.apsb.2018.08.009PMC PMC6437555

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Abstract

Tyrosine phosphatase SHP2 is a promising drug target in cancer immunotherapy due to its bidirectional role in both tumor growth promotion and T-cell inactivation. Its allosteric inhibitor SHP099 is known to inhibit cancer cell growth both in vitro and in vivo. However, whether SHP099-mediated SHP2 inhibition retards tumor growth in vivo via anti-tumor immunity remains elusive. To address this, a CT-26 colon cancer xenograft model was established in mice since this cell line is insensitive to SHP099. Consequently, SHP099 minimally affected CT-26 tumor growth in immuno-deficient nude mice, but significantly decreased the tumor burden in CT-26 tumor-bearing mice with intact immune system. SHP099 augmented anti-tumor immunity, as shown by the elevated proportion of CD8+IFN-γ+ T cells and the upregulation of cytotoxic T-cell related genes including Granzyme B andPerforin, which decreased the tumor load. In addition, tumor growth in mice with SHP2-deficient T-cells was markedly slowed down because of enhanced anti-tumor responses. Finally, the combination of SHP099 and anti-PD-1 antibody showed a higher therapeutic efficacy than either monotherapy in controlling tumor growth in two colon cancer xenograft models, indicating that these agents complement each other. Our study suggests that SHP2 inhibitor SHP099 is a promising candidate drug for cancer immunotherapy.

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Authors: Zhao, M., Guo, W., Wu, Y., Yang, C., Zhong, L., Deng, G., Zhu, Y., Liu, W., Gu, Y., Lu, Y., Kong, L., Meng, X., Xu, Q., & Sun, Y.
Affiliations: State Key Laboratory of Pharmaceutical Biotechnology (CN)
Nanjing University of Chinese Medicine (CN)
Peking University (CN)
Jiangsu Province Hospital (CN)
Corresponding author: Meng, Xiangbao
Xu, Qiang
Sun, Yang
ORCID: Zhao, Mingxia
Guo, Wenjie
Wu, Yuanyuan
Yang, Chenxi
Zhu, Yuyu
Liu, Wen
Gu, Yanhong
Lu, Yin
Meng, Xiangbao
Xu, Qiang
Sun, Yang
Venue: Acta Pharmaceutica Sinica B
Publisher: Elsevier BV
Published: 2019-03
Volume: 9
Issue: 2
Pages: 304-315
ISSN: 2211-3835 (ISSN-L)
DOI: 10.1016/j.apsb.2018.08.009
PMC: PMC6437555
OpenAlex: W2891517856
Cited by: 190
References: 38
Citations by year: 2026: 15 · 2025: 25 · 2024: 25 · 2023: 18 · 2022: 37 · 2021: 27 · 2020: 33 · 2019: 10
FWCI: 6.23
Type: journal article
Language: en
Update notices: erratum (2025-05-01)
Open access: gold
doi.org
Licence: cc-by-nc-nd
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
creativecommons.org/licenses/by-nc-nd/4.0/ (vor)
Locations: Acta Pharmaceutica Sinica B (publishedVersion, cc-by-nc-nd)
Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
PubMed Central (publishedVersion, cc-by-nc-nd)
PubMed (publishedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders: National Natural Science Foundation of China (81673436, 81673437, 21472091, 81872877)
Nanjing University
Priority Academic Program Development of Jiangsu Higher Education Institutions
State Key Laboratory of Pharmaceutical Biotechnology (KF-GN-201703)
Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica (JKLPSE201802)
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, SHP099, protein tyrosine phosphatase inhibition, antitumor immunity, anti-PD-1 therapy, combination immunotherapy, colon cancer, CD8+ T cells, cytotoxic T lymphocytes, T cell exhaustion, allosteric inhibitors

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SHP2 inhibition triggers anti-tumor immunity and synergizes with PD-1 blockade

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