Negative regulation of natural killer cell in tumor tissue and peripheral blood of oral squamous cell carcinoma

Dutta, Anupam; Banerjee, Arunabha; Saikia, Nabajyoti; Phookan, Jyotirmoy; Baruah, Munindra Narayan; Baruah, Satyabrat Malla Bujar

doi:10.1016/j.cyto.2015.09.006

Cited by 37 publications

(24 citation statements)

References 48 publications

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“…Additionally, the mouse strain used in our studies, NSG, is immune-deficient, lacking mature T cells, B cells, and NK cells. TGF-β signaling has been shown to help tumor cells escape from the immune-surveillance through targeting both T cells and NK cells within the tumor microenvironment [ 48 , 49 , 50 ]. Use of an immune-deficient mouse strain limits our ability to study the effect of LY on immune function, which may be quite important [ 51 ].…”

Section: Discussionmentioning

confidence: 99%

LY2157299 Monohydrate, a TGF-βR1 Inhibitor, Suppresses Tumor Growth and Ascites Development in Ovarian Cancer

Zhang

Hou

Evans

et al. 2018

Cancers

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Transforming growth factor beta (TGF-β) signaling has pleiotropic functions regulating cancer initiation, development, and metastasis, and also plays important roles in the interaction between stromal and cancer cells, making the pathway a potential therapeutic target. LY2157299 monohydrate (LY), an inhibitor of TGF-β receptor I (TGFBRI), was examined for its ability to inhibit ovarian cancer (OC) growth both in high-grade serous ovarian cancer (HGSOC) cell lines and xenograft models. Immunohistochemistry, qRT-PCR, and Western blot were performed to study the effect of LY treatment on expression of cancer- and fibroblast-derived genes. Results showed that exposure to TGF-β1 induced phosphorylation of SMAD2 and SMAD3 in all tested OC cell lines, but this induction was suppressed by pretreatment with LY. LY alone inhibited the proliferation, migration, and invasion of HGSOC cells in vitro. TGF-β1-induced fibroblast activation was blocked by LY. LY also delayed tumor growth and suppressed ascites formation in vivo. In addition, independent of tumor inhibition, LY reduces ascites formation in vivo. Using OVCAR8 xenograft specimens we confirmed the inhibitory effect of LY on TGF-β signaling and tumor stromal expression of collagen type XI chain 1 (COL11A1) and versican (VCAN). These observations suggest a role for anti-TGF-β signaling-directed therapy in ovarian cancer.

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Section: Discussionmentioning

confidence: 99%

LY2157299 Monohydrate, a TGF-βR1 Inhibitor, Suppresses Tumor Growth and Ascites Development in Ovarian Cancer

Zhang

Hou

Evans

et al. 2018

Cancers

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“…Within the TME, the transforming growth factor beta (TGFβ) family has an important role in tumor immune evasion, leading to tumor progression and metastasis (4, 5). The clinical importance of TGFβ1 in suppressing NK cells is indicated by two studies of patients with breast or squamous cell carcinoma (6, 7). Among the TGFβ family, TGFβ1 is the most commonly up-regulated in tumor cells (5, 8).…”

Section: Introductionmentioning

confidence: 99%

TGFβR1 Blockade with Galunisertib (LY2157299) Enhances Anti-Neuroblastoma Activity of the Anti-GD2 Antibody Dinutuximab (ch14.18) with Natural Killer Cells

Tran

Wan

Sheard

et al. 2017

Clinical Cancer Research

106

100

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Purpose Immunotherapy of high-risk neuroblastoma using the anti-GD2 antibody dinutuximab induces antibody-dependent cell-mediated cytotoxicity (ADCC). Galunisertib, an inhibitor of TGFβR1, was examined for its ability to enhance the efficacy of dinutuximab in combination with human ex vivo activated NK (aNK) cells against neuroblastoma. Experimental Design TGFB1 and TGFBR1 mRNA expression was determined for 249 primary neuroblastoma tumors by microarray analysis. The ability of galunisertib to inhibit SMAD activity induced by neuroblastoma patient blood and bone marrow plasmas in neuroblastoma cells was tested. The impact of galunisertib on TGFβ1-induced inhibition of aNK cytotoxicity and ADCC in vitro and on anti-neuroblastoma activity in NSG mice was determined. Results Neuroblastomas express TGFB1 and TGFBR1 mRNA. Galunisertib suppressed SMAD activation in neuroblastoma cells induced by exogenous TGFβ1 or by patient blood and bone marrow plasma, and suppressed SMAD2 phosphorylation in human neuroblastoma cells growing in NSG mice. In NK cells treated in vitro with exogenous TGFβ1, galunisertib suppressed SMAD2 phosphorylation and restored the expression of DNAM-1, NKp30, and NKG2D cytotoxicity receptors, TRAIL death ligand, the release of perforin and granzyme A, and the direct cytotoxicity and ADCC of aNK cells against NB cells. Addition of galunisertib to adoptive cell therapy with aNK cells plus dinutuximab reduced tumor growth and increased survival of mice injected with two neuroblastoma cell lines or a patient-derived xenograft. Conclusion Galunisertib suppresses activation of SMAD2 in neuroblastomas and aNK cells, restores NK cytotoxic mechanisms, and increases the efficacy of dinutuximab with aNK cells against neuroblastoma tumors.

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“…Regulated by an integration of inhibitory and activating receptors, NK cells display at least two effector functions against the tumor cells: they can mediate direct cytotoxic activity through degranulation and they are also able to produce a variety of antitumor active and immunoregulatory cytokines such as IFN-γ, TNF-α [6]. NK cells are reported to participate in the destruction of various types of tumors [7–10]. However, their exact contribution to the control of human solid tumors, including ccRCC, remains disputed due to functional defects of TINK cells, resulting in tumor cells escaping from NK cell attack [11].…”

Section: Introductionmentioning

confidence: 99%

Negative regulation of tumor-infiltrating NK cell in clear cell renal cell carcinoma patients through the exosomal pathway

et al. 2017

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Natural killer cells are the key components in tumor immunity and defects in function are necessary for tumor immune escape. Emerging studies on tumor cell-derived exosomes have shown the biological significance in tumor microenvironment, but the underlying role of exosomes in regulating natural killer cells functions in clear cell renal cell carcinoma patients remains unknown. Firstly, we precisely characterized the phenotype and function of natural killer cells in clear cell renal cell carcinoma patients vs healthy controls. With an inhibitory phenotype, tumor-infiltrating natural killer cells exhibited poor cytotoxic capacity and deficient potential to produce cytokines compared with natural killer cells from tumor margin tissue and non-tumor tissue. Next, we revealed that primary tumor cells trigged natural killer cell dysfunction in an exosome-dependent manner. Interestingly, exosomes from primary tumor cells were preferentially enriched with TGF-β1 which acted as important mediator of natural killer cell functional deficiency. In vitro culture of exosomes induced natural killer cell dysfunction mediated by activation of the TGF-β/SMAD signaling pathway, and abrogated by knockdown TGF-β. Our data indicate that exosomes from clear cell renal cell carcinoma induce natural killer cells dysfunction by regulating the TGF-β/SMAD pathway to evade innate immune surveillance.

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Negative regulation of natural killer cell in tumor tissue and peripheral blood of oral squamous cell carcinoma

Cited by 37 publications

References 48 publications

LY2157299 Monohydrate, a TGF-βR1 Inhibitor, Suppresses Tumor Growth and Ascites Development in Ovarian Cancer

LY2157299 Monohydrate, a TGF-βR1 Inhibitor, Suppresses Tumor Growth and Ascites Development in Ovarian Cancer

TGFβR1 Blockade with Galunisertib (LY2157299) Enhances Anti-Neuroblastoma Activity of the Anti-GD2 Antibody Dinutuximab (ch14.18) with Natural Killer Cells

Negative regulation of tumor-infiltrating NK cell in clear cell renal cell carcinoma patients through the exosomal pathway

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