Cd73: An Emerging Checkpoint for Cancer Immunotherapy

Chen, Siqi; Wainwright, Derek A.; Wu, Jennifer D.; Wan, Yong; Matei, Daniela; Zhang, Yi; Zhang, Bin

doi:10.2217/imt-2018-0200

Cited by 91 publications

(93 citation statements)

References 156 publications

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“…Immune suppression based on alternative regulation of immune checkpoint proteins, which results in T‐cell exhaustion, contributes to cancer development and progression . Increasing findings have shown that several immune checkpoint proteins play a key role in negatively regulating T‐cell activation, including programmed cell death receptor‐1 (PD‐1), cytotoxic T lymphocyte‐associated molecule‐4 (CTLA‐4), T‐cell immunoglobulin mucin‐domain‐containing‐3 (Tim‐3), T‐cell lymphocyte activation gene‐3 (LAG‐3), and B and T lymphocyte attenuator (BTLA) .…”

Section: Introductionmentioning

confidence: 99%

“…Immune suppression based on alternative regulation of immune checkpoint proteins, which results in T-cell exhaustion, contributes to cancer development and progression. 1,2 Increasing findings have shown that several immune checkpoint proteins play a key role in negatively regulating T-cell activation, including programmed cell death receptor- is disrupting the tumor microenvironment and restoring T-cell immune function. 8,9 Similarly, PD-1 inhibitors have been used for refractory and relapse lymphoma in clinical trials.…”

Section: Introductionmentioning

confidence: 99%

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Higher frequency of the CTLA‐4⁺LAG‐3⁺ T‐cell subset in patients with newly diagnosed acute myeloid leukemia

Chen

Tan

Huang

et al. 2019

Asia-Pac J Clncl Oncology

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Aim Immune suppression based on alternative regulation of immune checkpoint proteins, for example, programmed cell death receptor‐1 (PD‐1) and cytotoxic T lymphocyte–associated molecule‐4 (CTLA‐4), which results in T‐cell exhaustion, contributes to cancer development and progression. In this study, we sought to characterize the distribution of CTLA‐4 and T‐cell lymphocyte activation gene‐3 (LAG‐3) expression on exhausted T cells in different T‐cell subsets from patients with acute myeloid leukemia (AML). Methods The coexpression of CTLA‐4 and LAG‐3 on exhausted CD244+ and CD57+ T cells from the CD3+, CD4+, and CD8+ T‐cell subsets in peripheral blood from 12 patients with newly diagnosed AML was analyzed by multicolor flow cytometry assay. Results A significantly higher percentage of CTLA‐4+CD3+, CD4+ and CD8+ T cells was found in patients with AML. In addition, higher numbers of both CTLA‐4+CD244+ and CTLA‐4+CD57+CD3+ T cells were detected. Interestingly, the increased CTLA‐4+CD244+ T cells were predominantly CD4+ T cells. In contrast, the increased CTLA‐4+CD57+ T cells primarily consisted of the CD8+ T‐cell subset. A high proportion of LAG‐3+ T cells was found in only a few cases with AML; however, a significantly higher proportion of coexpression of CTLA‐4 and LAG‐3 in the CD3+ and CD8+ T‐cell subsets was detected. Conclusion We for the first time observed higher CTLA‐4+CD244+CD4+, CTLA‐4+CD57+CD8+, CTLA‐4+LAG‐3+CD3+ and CTLA‐4+LAG‐3+CD8+ T cells in patients with AML, whereas the upregulated expression of LAG‐3 on T cells was only found in a subset of the cases. These data may provide further information by complementing the heterogeneity of immune checkpoints expression in AML.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Higher frequency of the CTLA‐4⁺LAG‐3⁺ T‐cell subset in patients with newly diagnosed acute myeloid leukemia

Chen

Tan

Huang

et al. 2019

Asia-Pac J Clncl Oncology

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“…It was demonstrated that extracellular adenosine accumulated in the TME was largely produced by CD39/CD73 (20). The CD73-expressing tumor cells negatively regulated antitumor T-cell response and also promoted T cell apoptosis (35). In many cancer types, silencing CD73 inhibited tumor cell proliferation, viability, cell-cycle progression, leading to increased cell apoptosis (36,37).…”

Section: Discussionmentioning

confidence: 99%

MiRNA-340-5p Mediates the Functional and Infiltrative Promotion of Tumor-Infiltrating CD8+ T Lymphocytes in Human Diffuse Large B Cell Lymphoma

Liu

et al. 2020

Preprint

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Background: CD8+ tumor-infiltrating T lymphocytes (T-TILs) in the tumor microenvironment (TME) play an important role in tumor development, and miRNAs regulate tumor cell interactions with the microenvironment. T-TIL-based tumor immunotherapy provides a promising treatment strategy in diffuse large B-cell lymphoma (DLBCL). MiRNAs tend to be attractive targets for novel antitumor interventions.Methods: Weighted gene coexpression network analysis (WGCNA), CIBERSORT analysis and Cox regression analysis were used to identify CD8+ T-TIL-related miRNAs. RT-PCR, western blotting, immunohistochemistry (IHC), luciferase reporter assay, coimmunoprecipitation and ubiquitination analyses were used to detect miRNA, mRNA and protein expression and their combination. The viability and function of CD8+ T cells after stimulation were evaluated by enzyme-linked immunosorbent assay (ELISA), cytotoxicity assay, functional avidity assessment, flow cytometry and Cell Counting Kit-8 (CCK-8) assay. DLBCL cell lines, primary cells and a murine xenograft model established with A20 cell injection were used as in vitro and in vivo experimental models.Results: MiR-340-5p was positively correlated with CD8+ T-TILs in DLBCL patients, and KMT5A was a direct target gene of miR-340-5p. CD8+ T-cell function was significantly enhanced by miR-340-5p mimics both in vitro and in vivo, which was reversed by KMT5A overexpression. We demonstrated that COP1/CD73 was involved in the downstream mechanism of the miR-340-5p/KMT5A axis involving ubiquitination. In vivo, we validated an improved CD8+ T-TIL infiltration rate and tumor suppression with miR-340-5p treatment. Furthermore, miR-340-5p directly regulated the biological activity of DLBCL cells without CD8+ T-cell participation.Conclusions: MiR-340-5p promoted CD8+ T-TIL infiltration and antitumor function by regulating KMT5A and COP1 and further activating CD73 ubiquitination. MiR-340-5p is potentially a novel target for DLBCL immunotherapy.

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“…PABPC1 can combine with adenylate-rich sequences in mRNA under the action of high a nity, which plays an important role in post-transcriptional regulation of genes and is also involved in many metabolic pathways of mRNA, including adenylate polymerization/adenylation, mRNA transport, mRNA translation, microRNA degradation related regulation [45]. NT5E is a ubiquitously expressed glycosylphatidylinositol-xed glycoprotein, which can convert extracellular adenosine 5'-monophosphate to adenosine, and promote tumor development by inhibiting the anti-tumor immune response and promoting angiogenesis [46,47].…”

Section: Discussionmentioning

confidence: 99%

Stem Cell-Related Prognostic Signature for Lung Adenocarcinoma

Huang

Shi

Zhou

et al. 2020

Preprint

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Background: Adenocarcinoma is characterized by high infiltration and negative growth, which is easy to invade the walls of blood vessels and lymphatic vessels. The function of the stem cell population is to control and maintain cell regeneration. Therefore, it is necessary to study the prognostic value of stem cells in LUAD.Methods: Stem cells signature construction relies on the univariate, least absolute shrinkage operator (LASSO) and multivariate Cox regression analysis. Risk plot, Kaplan-Meier analysis and the area under ROC (AUC) are verified the accuracy of the signature in GEO (GSE20319 and GSE42127) and TCGA cohort respectively. What's more, to further improve persuasiveness, we conducted nomogram, drug efficacy analysis, immune infiltration analysis, and compared the relationship between mRNA stem cell index (mRNAsi) and signature.Result: The patients were divided into two groups via the cutoff of risk score; it can be seen that the low-risk group has better survival. The robust signature that contains ten stem cells is independent prognostic factors for LUAD (C6orf62, DNER, NELL2, LATS2, LGR5, PTPRO, LRIG1, PABPC1, NT5E and SET). The nomogram showed that 1-year (0.805), 3-year (0.773), and 5-year (0.765) survival rates of the signature we constructed were all greater than 0.7, indicating that our signature was very feasible.Conclusion: The signature can be used as a reliable and convenient tool for lung adenocarcinoma.

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Cd73: An Emerging Checkpoint for Cancer Immunotherapy

Cited by 91 publications

References 156 publications

Higher frequency of the CTLA‐4⁺LAG‐3⁺ T‐cell subset in patients with newly diagnosed acute myeloid leukemia

Higher frequency of the CTLA‐4⁺LAG‐3⁺ T‐cell subset in patients with newly diagnosed acute myeloid leukemia

MiRNA-340-5p Mediates the Functional and Infiltrative Promotion of Tumor-Infiltrating CD8+ T Lymphocytes in Human Diffuse Large B Cell Lymphoma

Stem Cell-Related Prognostic Signature for Lung Adenocarcinoma

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Cd73: An Emerging Checkpoint for Cancer Immunotherapy

Cited by 91 publications

References 156 publications

Higher frequency of the CTLA‐4+LAG‐3+ T‐cell subset in patients with newly diagnosed acute myeloid leukemia

Higher frequency of the CTLA‐4+LAG‐3+ T‐cell subset in patients with newly diagnosed acute myeloid leukemia

MiRNA-340-5p Mediates the Functional and Infiltrative Promotion of Tumor-Infiltrating CD8+ T Lymphocytes in Human Diffuse Large B Cell Lymphoma

Stem Cell-Related Prognostic Signature for Lung Adenocarcinoma

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Higher frequency of the CTLA‐4⁺LAG‐3⁺ T‐cell subset in patients with newly diagnosed acute myeloid leukemia

Higher frequency of the CTLA‐4⁺LAG‐3⁺ T‐cell subset in patients with newly diagnosed acute myeloid leukemia