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SHP2 deneddylation mediates tumor immunosuppression in colon cancer via the CD47/SIRPα axis

SIPRα on macrophages binds with CD47 to resist proengulfment signals, but how the downstream signal of SIPRα controls tumor-infiltrating macrophages (TIMs) is still poorly clarified. Here, we report that the CD47/signal regulatory protein α (SIRPα) axis requires the deneddylation of tyrosine phospha...

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Autores principales: Li, Yiqing, Zhou, Hui, Liu, Pan, Lv, Dandan, Shi, Yichun, Tang, Bufu, Xu, Jiaqi, Zhong, Tingting, Xu, Wangting, Zhang, Jie, Zhou, Jianying, Ying, Kejing, Zhao, Yongchao, Sun, Yi, Jiang, Zhinong, Cheng, Hongqiang, Zhang, Xue, Ke, Yuehai
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Clinical Investigation 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9927946/
https://www.ncbi.nlm.nih.gov/pubmed/36626230
http://dx.doi.org/10.1172/JCI162870
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author Li, Yiqing
Zhou, Hui
Liu, Pan
Lv, Dandan
Shi, Yichun
Tang, Bufu
Xu, Jiaqi
Zhong, Tingting
Xu, Wangting
Zhang, Jie
Zhou, Jianying
Ying, Kejing
Zhao, Yongchao
Sun, Yi
Jiang, Zhinong
Cheng, Hongqiang
Zhang, Xue
Ke, Yuehai
author_facet Li, Yiqing
Zhou, Hui
Liu, Pan
Lv, Dandan
Shi, Yichun
Tang, Bufu
Xu, Jiaqi
Zhong, Tingting
Xu, Wangting
Zhang, Jie
Zhou, Jianying
Ying, Kejing
Zhao, Yongchao
Sun, Yi
Jiang, Zhinong
Cheng, Hongqiang
Zhang, Xue
Ke, Yuehai
author_sort Li, Yiqing
collection PubMed
description SIPRα on macrophages binds with CD47 to resist proengulfment signals, but how the downstream signal of SIPRα controls tumor-infiltrating macrophages (TIMs) is still poorly clarified. Here, we report that the CD47/signal regulatory protein α (SIRPα) axis requires the deneddylation of tyrosine phosphatase SHP2. Mechanistically, Src homology region 2–containing protein tyrosine phosphatase 2 (SHP2) was constitutively neddylated on K358 and K364 sites; thus, its autoinhibited conformation was maintained. In response to CD47-liganded SIRPα, SHP2 was deneddylated by sentrin-specific protease 8 (SENP8), which led to the dephosphorylation of relevant substrates at the phagocytic cup and subsequent inhibition of macrophage phagocytosis. Furthermore, neddylation inactivated myeloid-SHP2 and greatly boosted the efficacy of colorectal cancer (CRC) immunotherapy. Importantly, we observed that supplementation with SHP2 allosteric inhibitors sensitized immune treatment–resistant CRC to immunotherapy. Our results emphasize that the CRC subtype that is unresponsive to immunotherapy relies on SIRPα(hi)SHP2(hi)NEDD8(lo) TIMs and highlight the need to further explore the strategy of SHP2 targeting in CRC therapy.
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spelling pubmed-99279462023-02-15 SHP2 deneddylation mediates tumor immunosuppression in colon cancer via the CD47/SIRPα axis Li, Yiqing Zhou, Hui Liu, Pan Lv, Dandan Shi, Yichun Tang, Bufu Xu, Jiaqi Zhong, Tingting Xu, Wangting Zhang, Jie Zhou, Jianying Ying, Kejing Zhao, Yongchao Sun, Yi Jiang, Zhinong Cheng, Hongqiang Zhang, Xue Ke, Yuehai J Clin Invest Research Article SIPRα on macrophages binds with CD47 to resist proengulfment signals, but how the downstream signal of SIPRα controls tumor-infiltrating macrophages (TIMs) is still poorly clarified. Here, we report that the CD47/signal regulatory protein α (SIRPα) axis requires the deneddylation of tyrosine phosphatase SHP2. Mechanistically, Src homology region 2–containing protein tyrosine phosphatase 2 (SHP2) was constitutively neddylated on K358 and K364 sites; thus, its autoinhibited conformation was maintained. In response to CD47-liganded SIRPα, SHP2 was deneddylated by sentrin-specific protease 8 (SENP8), which led to the dephosphorylation of relevant substrates at the phagocytic cup and subsequent inhibition of macrophage phagocytosis. Furthermore, neddylation inactivated myeloid-SHP2 and greatly boosted the efficacy of colorectal cancer (CRC) immunotherapy. Importantly, we observed that supplementation with SHP2 allosteric inhibitors sensitized immune treatment–resistant CRC to immunotherapy. Our results emphasize that the CRC subtype that is unresponsive to immunotherapy relies on SIRPα(hi)SHP2(hi)NEDD8(lo) TIMs and highlight the need to further explore the strategy of SHP2 targeting in CRC therapy. American Society for Clinical Investigation 2023-02-15 /pmc/articles/PMC9927946/ /pubmed/36626230 http://dx.doi.org/10.1172/JCI162870 Text en © 2023 Li et al. https://creativecommons.org/licenses/by/4.0/This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Article
Li, Yiqing
Zhou, Hui
Liu, Pan
Lv, Dandan
Shi, Yichun
Tang, Bufu
Xu, Jiaqi
Zhong, Tingting
Xu, Wangting
Zhang, Jie
Zhou, Jianying
Ying, Kejing
Zhao, Yongchao
Sun, Yi
Jiang, Zhinong
Cheng, Hongqiang
Zhang, Xue
Ke, Yuehai
SHP2 deneddylation mediates tumor immunosuppression in colon cancer via the CD47/SIRPα axis
title SHP2 deneddylation mediates tumor immunosuppression in colon cancer via the CD47/SIRPα axis
title_full SHP2 deneddylation mediates tumor immunosuppression in colon cancer via the CD47/SIRPα axis
title_fullStr SHP2 deneddylation mediates tumor immunosuppression in colon cancer via the CD47/SIRPα axis
title_full_unstemmed SHP2 deneddylation mediates tumor immunosuppression in colon cancer via the CD47/SIRPα axis
title_short SHP2 deneddylation mediates tumor immunosuppression in colon cancer via the CD47/SIRPα axis
title_sort shp2 deneddylation mediates tumor immunosuppression in colon cancer via the cd47/sirpα axis
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9927946/
https://www.ncbi.nlm.nih.gov/pubmed/36626230
http://dx.doi.org/10.1172/JCI162870
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