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SHP2 deneddylation mediates tumor immunosuppression in colon cancer via the CD47/SIRPα axis
Yiqing Li, … , Xue Zhang, Yuehai Ke
Yiqing Li, … , Xue Zhang, Yuehai Ke
Published January 10, 2023
Citation Information: J Clin Invest. 2023;133(4):e162870. https://doi.org/10.1172/JCI162870.
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Research Article Cell biology Article has an altmetric score of 3

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

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Abstract

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 SIRPαhiSHP2hiNEDD8lo TIMs and highlight the need to further explore the strategy of SHP2 targeting in CRC therapy.

Authors

Yiqing Li, Hui Zhou, Pan Liu, Dandan Lv, Yichun Shi, Bufu Tang, Jiaqi Xu, Tingting Zhong, Wangting Xu, Jie Zhang, Jianying Zhou, Kejing Ying, Yongchao Zhao, Yi Sun, Zhinong Jiang, Hongqiang Cheng, Xue Zhang, Yuehai Ke

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Figure 7

Neddylation of SHP2 promotes macrophage-mediated phagocytosis.

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Neddylation of SHP2 promotes macrophage-mediated phagocytosis.
(A) Norma...
(A) Normalized bead eating of BMDMs as indicated (n = 6). (B) Normalized bead eating of BMDMs as indicated (n = 6). (C) Representative TIRF images of BMDMs stained with pTyr, F-actin (phalloidin), and paxillin on ICAM-1–coated (100 nM) coverslips. Scale bar: 10 μm. (D) Representative TIRF images of MEFs stained with Talin1 on ICAM-1–coated (100 nM) coverslips (n = 6). Scale bars: 10 μm. (E) Western blot indicating tyrosine phosphorylation profile of subcellular fractionation of BMDMs. (F) Flow cytometry showed specific phagocytosis of hPDL1-expressing MC38 cells by indicated BMDMs (n = 3). (G–I) In vivo tumor cell recovery assay (n = 10). Schematic shows a 1:1 mixture of anti-mPDL1–opsonized or isotype–opsonized MC38 cells were injected i.p. into indicated mice. Peritoneal lavage fluid was required to calculate recovered tumor cells. Representative flow analysis plots of recovered tumor cells from mice (G). Data are represented as number of recovered tumor cells from mice (H). Data are represented as ratio between recovered tumor cells from mice that were differently opsonized (I). Data are represented as mean ± SD. *P < 0.05; ***P < 0.001; ****P < 0.0001; NS, P > 0.05. Two-tailed, unpaired Student’s t test (I); 1-way ANOVA followed by Tukey’s post hoc test (A, B, D, F, H).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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