PTEN at the interface of immune tolerance and tumor suppression

Brandmaier, Andrew; Hou, Shengqi; Demaria, Sandra; Formenti, Silvia C.; Shen, Wen Hong

doi:10.1007/s11515-017-1443-5

Cited by 20 publications

(16 citation statements)

References 84 publications

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“…Emerging evidence indicates that PTEN may have additional lipid phosphatase independent functions that are independent of the PI3K/AKT pathway, including those affecting tumor growth through modulation of the immune response and tumor microenvironment (TME) . In immune cells, PTEN is critical for cell maturation and activation . More recently, the secreted PTEN long protein (PTEN‐L) was also reported to be the key in activating the antiviral type I interferon (IFNI) response .…”

Section: Introductionmentioning

confidence: 99%

PTEN‐deficient prostate cancer is associated with an immunosuppressive tumor microenvironment mediated by increased expression of IDO1 and infiltrating FoxP3+ T regulatory cells

et al. 2019

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Background: Accumulating evidence shows that tumor cell-specific genomic changes can influence the cross talk between cancer cells and the surrounding tumor microenvironment (TME). Loss of the PTEN tumor suppressor gene is observed in 20% to 30% of prostate cancers (PCa) when first detected and the rate increases with PCa progression and advanced disease. Recent findings implicate a role for PTEN in cellular type I interferon response and immunosuppression in PCa. However, the way that PTEN inactivation alters antitumor immune response in PCa is poorly understood. Materials and Methods:To investigate the changes associated with PTEN loss and an immunosuppressive TME in PCa, we used CIBERSORT to estimate the relative abundance of 22 immune-cell types from 741 primary and 96 metastatic tumors. Our in silico findings were then validated by immunohistochemical analysis of immune cells and IDO1 and PDL1 checkpoint proteins in a cohort of 94 radical prostatectomy specimens.Results: FoxP3+ T regulatory cells (Tregs) were significantly increased in PTENdeficient PCa in all three public domain cohorts. Loss of PTEN in bone metastases was associated with lower CD8+ T-cell abundance, but in liver metastasis, FoxP3+ Tregs were present at higher levels. PTEN-deficient lymph node metastasis had a distinct profile, with high levels of CD8+ T cells. Moreover, we found that metastatic PCa presents higher abundance of FoxP3+ Treg when compared to primary lesions. Since PTEN-deficient tumors are likely to be immunosuppressed as a consequence of increased FoxP3+ Tregs, we then evaluated the localization and expression of IDO1, PDL1 immune checkpoints, and the corresponding density of FoxP3+ Treg and CD8+ T cells using our validation cohort (n = 94). We found that IDO1 protein expression and FoxP3+ Treg density were higher in neoplastic glands compared with benign adjacent tissue. Moreover, higher densities of FoxP3+ Treg cells in both stromal The Prostate. 2019;79:969-979.wileyonlinelibrary.com/journal/pros

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Section: Introductionmentioning

confidence: 99%

PTEN‐deficient prostate cancer is associated with an immunosuppressive tumor microenvironment mediated by increased expression of IDO1 and infiltrating FoxP3+ T regulatory cells

et al. 2019

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“…Emerging works suggest that PTEN might have additional functions in the tumor microenvironment including those affecting tumor growth through modulation of the immune response [30,31]. Host immune response against tumor cells is a tumor suppressor mechanism which provide a barrier to malignant transformation.…”

Section: Evidences For Immunosuppressive Tumour Microenvironment In Pmentioning

confidence: 99%

Is there a causal link between PTEN deficient tumors and immunosuppressive tumor microenvironment?

Çetintaş

Batada

2020

J Transl Med

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The PTEN tumor suppressor is the second most commonly inactivated gene across cancer types. While it's role in PI3K/AKT and DNA damage pathways are clear, increasing evidences suggest that PTEN may also promote anti-tumor immunity. PTEN-deficient tumors are characterized by (i) reduced levels of cytotoxic T cells, helper T cells and NK cells, (ii) elevated pro-oncogenic inflammatory cytokines like CCL2 and (iii) increased levels of immunosuppressive cells such as MDSCs and Tregs. An intriguing possibility is that link between PTEN and anti-tumor immunity is mediated by the interferon signaling pathway. In this review, we summarize the evidences for the mechanistic link between PTEN deficiency and immunosuppressive tumor microenvironment and the interferon signaling pathway. We further discuss how the link between these pathways can be exploited for development of personalized immunotherapy for patients with PTEN deficient tumors.

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“…The active‐site pocket of the PTEN phosphatase domain is both wide and deep enough which enables it to accommodate the substrates such as PI(3,4,5)P3 and some proteins. PTEN dephosphorylates PI(3,4,5)P3 to PI(4,5)P2, acting in direct opposition to the Class I PI3K enzymes in the regulation of PI3K‐AKT‐mTOR signaling pathway in immune cell proliferation, survival, and polarity . Interestingly, in the initiation stage of lymphocytes activation, PTEN is shown to potentially downregulate the formation of immunological synapse and signaling microclusters by tuning the levels of PI(3,4,5)P3 on the plasma membrane …”

Section: Amount and Metabolism Of Pi(45)p2 On The Plasma Membranementioning

confidence: 99%

A PI(4,5)P2‐derived “gasoline engine model” for the sustained B cell receptor activation

Wan

Shaheen

et al. 2019

Immunological Reviews

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To efficiently initiate activation responses against rare ligands in the microenvironment, lymphocytes employ sophisticated mechanisms involving signaling amplification. Recently, a signaling amplification mechanism initiated from phosphatidylinositol (PI) 4, 5‐biphosphate [PI(4,5)P2] hydrolysis and synthesis for sustained B cell activation has been reported. Antigen and B cell receptor (BCR) recognition triggered the prompt reduction of PI(4,5)P2 density within the BCR microclusters, which led to the positive feedback for the synthesis of PI(4,5)P2 outside of the BCR microclusters. At single molecule level, the diffusion of PI(4,5)P2 was slow, allowing for the maintenance of a PI(4,5)P2 density gradient between the inside and outside of the BCR microclusters and the persistent supply of PI(4,5)P2 from outside to inside of the BCR microclusters. Here, we review studies that have contributed to uncovering the molecular mechanisms of PI(4,5)P2‐derived signaling amplification model. Based on these studies, we proposed a “gasoline engine model” in which the activation of B cell signaling inside the microclusters is similar to the working principle of burning gasoline within the engine chamber of a gasoline engine. We also discuss the evidences showing the potential universality of this model and future prospects.

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PTEN at the interface of immune tolerance and tumor suppression

Cited by 20 publications

References 84 publications

PTEN‐deficient prostate cancer is associated with an immunosuppressive tumor microenvironment mediated by increased expression of IDO1 and infiltrating FoxP3+ T regulatory cells

PTEN‐deficient prostate cancer is associated with an immunosuppressive tumor microenvironment mediated by increased expression of IDO1 and infiltrating FoxP3+ T regulatory cells

Is there a causal link between PTEN deficient tumors and immunosuppressive tumor microenvironment?

A PI(4,5)P2‐derived “gasoline engine model” for the sustained B cell receptor activation

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