Loss of SHP-2 activity in CD4+ T cells promotes melanoma progression and metastasis

Zhang, Tao; Guo, Wenjie; Yang, Yang; Li, Wen; Guo, Lu; Gu, Yanhong; Shu, Yongqian; Wang, Lu; Wu, Xuefeng; Zhang, Hua; Ke, Yuehai; Sun, Yang; Shen, Yan; Xu, Qiang

doi:10.1038/srep02845

Cited by 30 publications

(25 citation statements)

References 40 publications

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“…In addition, immunogenic cancers developed in these mice with kinetics similar to the ones observed in the control groups (156). Along these lines, studies by others showed that the growth of immunogenic tumors in mice lacking Shp-2 in T cells was moderately retarded or accelerated, but even in the former case the effects on tumor growth were distant from the ones of PD-1-deficiency (154,160,161). One interpretation is that the therapeutic effects of PD-1 blockade are not largely mediated by T cells, a quite unlikely hypothesis in light of cytotoxic T cell depletion results (131,162).…”

Section: Shp-2 and Inhibitory Receptor Signaling In T And Nk Cellssupporting

confidence: 54%

“…The possibility that SHP-2 inhibits this cascade downstream of PD-1 is difficult to reconcile with its well-documented role in promoting it downstream of growth factor receptors. Moreover, despite the role of SHP-2 in TCR signaling remains controversial (79,(149)(150)(151)(152)(153)(154)(155)(156)(157), a positive effect on ERK engagement has been observed also in this context (149,152,153). The dichotomy in the effects of SHP-2 could be explained by a model in which IRs reduce the availability of the phosphatase, thus preventing its contribution to the ERK cascade, or by a very distinct regulation of SHP-2 activity downstream of IRs and growth factor receptors.…”

Section: Shp-2 and Inhibitory Receptor Signaling In T And Nk Cellsmentioning

confidence: 99%

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SHP-2 in Lymphocytes' Cytokine and Inhibitory Receptor Signaling

2019

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Somewhat counterintuitively, the tyrosine phosphatase SHP-2 (SH2 domain-containing protein tyrosine phosphatase-2) is crucial for the activation of extracellular signal-regulated kinase (ERK) downstream of various growth factor receptors, thereby exerting essential developmental functions. This phosphatase also deploys proto-oncogenic functions and specific inhibitors have recently been developed. With respect to the immune system, the role of SHP-2 in the signaling of cytokines relevant for myelopoiesis and myeloid malignancies has been intensively studied. The function of this phosphatase downstream of cytokines important for lymphocytes is less understood, though multiple lines of evidence suggest its importance. In addition, SHP-2 has been proposed to mediate the suppressive effects of inhibitory receptors (IRs) that sustain a dysfunctional state in anticancer T cells. Molecules involved in IR signaling are of potential pharmaceutical interest as blockade of these inhibitory circuits leads to remarkable clinical benefit. Here, we discuss the dichotomy in the functions ascribed to SHP-2 downstream of cytokine receptors and IRs, with a focus on T and NK lymphocytes. Further, we highlight the importance of broadening our understanding of SHP-2 ′ s relevance in lymphocytes, an essential step to inform on side effects and unanticipated benefits of its therapeutic blockade.

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Section: Shp-2 and Inhibitory Receptor Signaling In T And Nk Cellssupporting

confidence: 54%

Section: Shp-2 and Inhibitory Receptor Signaling In T And Nk Cellsmentioning

confidence: 99%

SHP-2 in Lymphocytes' Cytokine and Inhibitory Receptor Signaling

2019

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“…Whether the gene silencing of SHP-1/2 and SOCS-1 favors the progression from MGUS to MM remains to be determined. Finally, our work further emphasizes the implication of SHP-1 , SHP-2 and SOCS-1 genes as suppressors of tumor growth in different cancers [37, 50–52]. …”

Section: Discussionmentioning

confidence: 63%

Abnormal repression of SHP-1, SHP-2 and SOCS-1 transcription sustains the activation of the JAK/STAT3 pathway and the progression of the disease in multiple myeloma

et al. 2017

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Sustained activation of JAK/STAT3 signaling pathway is classically described in Multiple Myeloma (MM). One explanation could be the silencing of the JAK/STAT suppressor genes, through the hypermethylation of SHP-1 and SOCS-1, previously demonstrated in MM cell lines or in whole bone marrow aspirates. The link between such suppressor gene silencing and the degree of bone marrow invasion or the treatment response has not been evaluated in depth. Using real-time RT-PCR, we studied the expression profile of three JAK/STAT suppressor genes: SHP-1, SHP-2 and SOCS-1 in plasma cells freshly isolated from the bone marrows of MM patients and healthy controls. Our data demonstrated an abnormal repression of such genes in malignant plasma cells and revealed a significant correlation between such defects and the sustained activation of the JAK/STAT3 pathway during MM. The repressed expression of SHP-1 and SHP-2 correlated significantly with a high initial degree of bone marrow infiltration but was, unexpectedly, associated with a better response to the induction therapy. Collectively, our data provide new evidences that substantiate the contribution of JAK/STAT suppressor genes in the pathogenesis of MM. They also highlight the possibility that the decreased gene expression of SHP-1 and SHP-2 could be of interest as a new predictive factor of a favorable treatment response, and suggest new potential mechanisms of action of the therapeutic molecules. Whether such defect helps the progression of the disease from monoclonal gammopathy of unknown significance to MM remains, however, to be determined.

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“…At the basal level, there was no significant difference in the counts of CD4 + and CD8 + T cells, neither in the CD4-CD8 ratio in the spleen or the lymph nodes between WT and SHP2 CD4−/− mice [19]. Next, we examined whether SHP2-deficiency in CD4 + T cells impacts the colitis progression using DSS-induced colitis model.…”

Section: Resultsmentioning

confidence: 99%

T lymphocyte SHP2-deficiency triggers anti-tumor immunity to inhibit colitis-associated cancer in mice

Guo

Shen

et al. 2016

Oncotarget

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Nonresolving inflammation is involved in the initiation and progression process of tumorigenesis. Src homology 2 domain-containing tyrosine phosphatase 2 (SHP2) is known to inhibit acute inflammation but its role in chronic inflammation-associated cancer remains unclear. The role of SHP2 in T cells in dextran sulfate sodium (DSS)-induced colitis and azoxymethane-DSS-induced colitis-associated carcinogenesis was examined using SHP2CD4−/− conditional knockout mice. SHP2 deficiency in T cells aggravated colitis with increased level of pro-inflammatory cytokines including IFN-γ and IL-17A. In contrast, the SHP2CD4−/− mice developed much fewer and smaller tumors than wild type mice with higher level of IFN-γ and enhanced cytotoxicity of CD8+ T cells in the tumor and peritumoral areas. At the molecular level, STAT1 was hyper-phosphorylated in T cells lacking SHP2, which may account for the increased Th1 differentiation and IFN-γ secretion. IFN-γ neutralization or IFN-γ receptor knockout but not IL-17A neutralization, abrogated the anti-tumor effect of SHP2 knockout with lowered levels of perforin 1, FasL and granzyme B. Finally, the expression of granzyme B was negatively correlated with the malignancy of colon cancer in human patients. In conclusion, these findings suggest a new strategy to treat colitis-associated cancer via targeting SHP2.

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Loss of SHP-2 activity in CD4+ T cells promotes melanoma progression and metastasis

Cited by 30 publications

References 40 publications

SHP-2 in Lymphocytes' Cytokine and Inhibitory Receptor Signaling

SHP-2 in Lymphocytes' Cytokine and Inhibitory Receptor Signaling

Abnormal repression of SHP-1, SHP-2 and SOCS-1 transcription sustains the activation of the JAK/STAT3 pathway and the progression of the disease in multiple myeloma

T lymphocyte SHP2-deficiency triggers anti-tumor immunity to inhibit colitis-associated cancer in mice

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