The Role of Tumor-Derived Vesicles in the Regulation of Antitumor Immunity

Ukrainskaya, V. M.; Rubtsov, Yuri P.; Knorre, V. D.; Maschan, Mikhail; Gabibov, Alexander; Степанов, А. В.

doi:10.32607/20758251-2019-11-4-33-41

Cited by 11 publications

(10 citation statements)

References 84 publications

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“…Of note, another open, but highly interesting question is the sensitivity of CD8 + T cells toward priming followed by anti-CD3/CD28 stimulation. Two major mechanisms by which TEV can contribute to tumor evasion are the initiation of apoptosis in cytotoxic CD8 + T cells and the conversion of conventional CD4 + T cells into regulatory T cells ( 48 ). Thus, the sensitivity of CD8 + T cells to priming with sHLA-G forms observed in our study might be explained by our lack of emphasis on the regulatory phenotype of CD4 + T cells biasing the analyses toward the CD8 + T cell subpopulation.…”

Section: Discussionmentioning

confidence: 99%

Soluble HLA-G and HLA-G Bearing Extracellular Vesicles Affect ILT-2 Positive and ILT-2 Negative CD8 T Cells Complementary

et al. 2020

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Tumor immune escape is associated with both, the expression of immune checkpoint molecules on peripheral immune cells and soluble forms of the human leukocyte antigen-G (HLA-G) in the blood, which are consequently discussed as clinical biomarker for disease status and outcome of cancer patients. HLA-G preferentially interacts with the inhibitory receptor immunoglobulin-like transcript (ILT) receptor-2 in the blood and can be secreted as free soluble molecules (sHLA-G) or via extracellular vesicles (EV). To investigate the contribution of these two forms to the expression of checkpoint molecules in peripheral blood, we primed peripheral blood mononuclear cells with purified soluble sHLA-G1 protein, or EV preparations derived from SUM149 cells transfected with membrane-bound HLA-G1 or control vector prior to anti-CD3/CD28 T cell activation. Our study demonstrated that priming of PBMC with sHLA-G1 protein prior to 48 h activation resulted in enhanced frequencies of ILT-2 expressing CD8 + T cells, and in an upregulation of immune checkpoint molecules CTLA-4, PD-1, TIM-3, and CD95 exclusively on ILT-2 positive CD8 + T cells. In contrast, when PBMC were primed with EV (containing HLA-G1 or not) upregulation of CTLA-4, PD-1, TIM-3, and CD95 occurred exclusively on ILT-2 negative CD8 + T cells. Taken together, our data suggest that priming with sHLA-G forms induces a pronounced immunosuppressive/exhausted phenotype and that priming with sHLA-G1 protein or EV derived from HLA-G1 positive or negative SUM149 cells affects CD8 + T cells complementary by targeting either the ILT-2 positive or negative subpopulation, respectively, after T cell activation.

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Section: Discussionmentioning

confidence: 99%

Soluble HLA-G and HLA-G Bearing Extracellular Vesicles Affect ILT-2 Positive and ILT-2 Negative CD8 T Cells Complementary

et al. 2020

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“…Exosomes, small membranous sacs of endocytic origin (30–150 nm), are considered as intercellular messengers that can carry a large number of macromolecular cargos, including proteins, mRNA, lipids, and miRNA ( Wen et al, 2016 ; Bach et al, 2017 ; Ruivo et al, 2017 ; Su et al, 2021 ). Studies have found that exosomes derived from tumors carry immunosuppressive proteins, including PD-1, CTLA-4, FasL, TRAIL, CD39, and CD73, which induce apoptosis and depletion of T lymphocytes to achieve tumor immune escape ( Whiteside, 2013 ; Ukrainskaya et al, 2019 ; Benecke et al, 2021 ). Cytotoxic T lymphocyte antigen 4 (CTLA-4), a member of the immune protein superfamily, competes with the T cell co-stimulator CD28 for binding to CD80 and CD86 with a higher affinity to antigen-presenting cells during the priming phase in the lymph nodes and conveys inhibitory signals within the T cells ( Van Coillie et al, 2020 ; Goenka et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Exosome CTLA-4 Regulates PTEN/CD44 Signal Pathway in Spleen Deficiency Internal Environment to Promote Invasion and Metastasis of Hepatocellular Carcinoma

Wang

Mao

et al. 2021

Front. Pharmacol.

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Hepatocellular carcinoma (HCC) is one of the most common primary cancers, and its pathogenesis is complicated and difficult to screen. Currently, there is no effective treatment. In traditional Chinese medicine, a large proportion of patients with HCC have been diagnosed with spleen deficiency (SD) syndrome and treated with tonifying traditional Chinese medicine, which has significant clinical efficacy. However, the role and molecular mechanism of SD in HCC remain unclear. In this study, 40 mice were randomly divided into four groups: control, SD, HCC, and SD-HCC groups. The liver cancer model of SD was established by reserpine induction and orthotopic transplantation. The effects of SD on the proliferation, apoptosis, invasion, and metastasis of HCC cells were studied by cell proliferation, cell apoptosis, cell scratch, and transwell assay. We found that compared with the HCC group, the protein expressions of cytotoxic T lymphocyte antigen 4 (CTLA-4), programmed cell death protein 1 (PD-1), phosphatase and tensin homolog (PTEN), and AKT (also known as protein kinase B or PKB) in the exosomes of the SD-HCC group were upregulated. In addition, the metastases and self-renewal of exosomes in the SD-HCC group were more aggressive than those in the HCC group, which could be partially reversed with the addition of CTLA-4 inhibitors. Further studies showed that in the internal environment of SD, CTLA-4 promoted tumor invasion and metastasis by regulating the PTEN/CD44 pathway. In conclusion, our findings suggest that during SD in the internal environment, exosome CTLA-4 regulates the PTEN/CD44 signal pathway to promote the proliferation, self-renewal, and metastasis of liver cancer.

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“…Qu et al 2 also found that lncARSR could be secreted from resistant cells via exosome, transforming sunitinib-sensitive cells into resistant cells, thereby disseminating drug resistance. Other research has demonstrated the role of the exosomes in tumoral cross talk with immune cells 36 . Yang et al .…”

Section: Discussionmentioning

confidence: 99%

Repurposing ketoconazole as an exosome directed adjunct to sunitinib in treating renal cell carcinoma

Greenberg

Kim

Moustafa

et al. 2021

Sci Rep

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Renal Cell Carcinoma (RCC) is the most common form of kidney cancer, with clear cell RCC (ccRCC) representing about 85% of all RCC tumors. There are limited curable treatments available for metastatic ccRCC because this disease is unresponsive to conventional targeted systemic pharmacotherapy. Exosomes (Exo) are small extracellular vesicles (EVs) secreted from cancer cells with marked roles in tumoral signaling and pharmacological resistance. Ketoconazole (KTZ) is an FDA approved anti-fungal medication which has been shown to suppress exosome biogenesis and secretion, yet its role in ccRCC has not been identified. A time-course, dose-dependent analysis revealed that KTZ selectively decreased secreted Exo in tumoral cell lines. Augmented Exo secretion was further evident by decreased expression of Exo biogenesis (Alix and nSMase) and secretion (Rab27a) markers. Interestingly, KTZ-mediated inhibition of Exo biogenesis was coupled with inhibition of ERK1/2 activation. Next, selective inhibitors were employed and showed ERK signaling had a direct role in mediating KTZ’s inhibition of exosomes. In sunitinib resistant 786-O cells lines, the addition of KTZ potentiates the efficacy of sunitinib by causing Exo inhibition, decreased tumor proliferation, and diminished clonogenic ability of RCC cells. Our findings suggest that KTZ should be explored as an adjunct to current RCC therapies.

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The Role of Tumor-Derived Vesicles in the Regulation of Antitumor Immunity

Cited by 11 publications

References 84 publications

Soluble HLA-G and HLA-G Bearing Extracellular Vesicles Affect ILT-2 Positive and ILT-2 Negative CD8 T Cells Complementary

Soluble HLA-G and HLA-G Bearing Extracellular Vesicles Affect ILT-2 Positive and ILT-2 Negative CD8 T Cells Complementary

Exosome CTLA-4 Regulates PTEN/CD44 Signal Pathway in Spleen Deficiency Internal Environment to Promote Invasion and Metastasis of Hepatocellular Carcinoma

Repurposing ketoconazole as an exosome directed adjunct to sunitinib in treating renal cell carcinoma

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