scholarly journals The regulation of immune checkpoints by the hypoxic tumor microenvironment

PeerJ ◽  
2021 ◽  
Vol 9 ◽  
pp. e11306
Author(s):  
Min Hu ◽  
Yongfu Li ◽  
Yuting Lu ◽  
Miao Wang ◽  
Yingrui Li ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Immune Escape ◽  
Epithelial Mesenchymal Transition ◽  
Malignant Tumors ◽  
Checkpoint Inhibitors ◽  
New Drugs ◽  
Immune Checkpoints ◽  
Mesenchymal Transition ◽  
Programmed Death ◽  
Domain 3

The tumor microenvironment (TME) influences the occurrence and progression of tumors, and hypoxia is an important characteristic of the TME. The expression of programmed death 1 (PD1)/programmed death-ligand 1 (PDL1), cytotoxic T-lymphocyte-associated antigen 4 (CTLA4), and other immune checkpoints in hypoxic malignant tumors is often significantly increased, and is associated with poor prognosis. The application of immune checkpoint inhibitors (ICIs) for treating lung cancer, urothelial carcinoma, and gynecological tumors has achieved encouraging efficacy; however, the rate of efficacy of ICI single-drug treatment is only about 20%. In the present review, we discuss the possible mechanisms by which the hypoxic TME regulates immune checkpoints. By activating hypoxia-inducible factor-1α (HIF-1α), regulating the adenosine (Ado)-A2aR pathway, regulating the glycolytic pathway, and driving epithelial-mesenchymal transition (EMT) and other biological pathways, hypoxia regulates the expression levels of CTLA4, PD1, PDL1, CD47, lymphocyte activation gene 3 (LAG3), T-cell immunoglobulin and mucin domain 3 (TIM3), and other immune checkpoints, which interfere with the immune effector cell anti-tumor response and provide convenient conditions for tumors to escape immune surveillance. The combination of HIF-1α inhibitors, Ado-inhibiting tumor immune microenvironment regulatory drugs, and other drugs with ICIs has good efficacy in both preclinical studies and phase I-II clinical studies. Exploring the effects of TME hypoxia on the expression of immune checkpoints and the function of infiltrating immune cells has greatly clarified the relationship between the hypoxic TME and immune escape, which is of great significance for the development of new drugs and the search for predictive markers of the efficacy of immunotherapy for treating malignant tumors. In the future, combination therapy with hypoxia pathway inhibitors and ICIs may be an effective anti-tumor treatment strategy.

scholarly journals Characterization of clinical significance of PD-1/PD-Ls expression and methylation in patients with low grade glioma

2020 ◽  
Author(s):  
Jie Mei ◽  
Yun Cai ◽  
Rui Xu ◽  
Xuejing Yang ◽  
Weijian Zhou ◽  
...  
Keyword(s):  
Clinical Significance ◽  
Survival Data ◽  
Immune Escape ◽  
Checkpoint Inhibitors ◽  
Expression Patterns ◽  
Methylation Status ◽  
Low Grade Glioma ◽  
Immune Checkpoints ◽  
Low Grade ◽  
Programmed Death

AbstractBackgroundImmune checkpoints play crucial roles in immune escape of cancer cells. However, the exact prognostic values of expression and methylation of programmed death 1 (PD-1), programmed death-ligand 1 (PD-L1) and PD-L2 in low-grade glioma (LGG) have not been defined yet.MethodsA total of 514 LGG samples from TCGA dataset containing both PD-1, PD-L1 and PD-L2 expression, DNA methylation, and survival data were enrolled into our study. The clinical significance of PD-1/PD-Ls expression and methylation in LGG were explored. Besides, the correlation between PD-1/PD-Ls expression and methylation with the infiltration levels of tumor-infiltrating immune cells (TIICs) was assessed. Moreover, GO enticement analysis of PD-1/PD-Ls co-expressed genes was performed as well. R 3.6.2 and GraphPad Prism 8 were applied as main tools for the statistical analysis and graphical exhibition.ResultsPD-1/PD-Ls had distinct co-expression patterns in LGG tissues. The expression and methylation status of PD-1/PD-Ls seemed to be various in different LGG subtypes. Besides, upregulated PD-1/PD-Ls expression and hypo-methylation of PD-1/PD-Ls were associated with worse survival in LGG patients. In addition, PD-1/PD-Ls expression was revealed to be positively associated with TIICs infiltration, while their methylation was negatively associated with TIICs infiltration. Moreover, the PD-1/PDLs correlated gene profiles screening and Gene Ontology (GO) enrichment analysis uncovered that PD-1/PDLs and their positively correlated gene mainly participated in immune response related biological processes.ConclusionsHigh expression and hypo-methylation of PD-1/PD-Ls significantly correlated with unfavorable survival in LGG patients, suggesting LGG patients may benefit from PD1/PD-Ls checkpoint inhibitors treatment.

scholarly journals The High Expression of CD276/HAVCR2 and CD163 is an Adverse Immune Subtype of Glioblastoma and is Closely Related to Epithelial-Mesenchymal Transition

2020 ◽  
Author(s):  
Xiaohong Hou ◽  
Guiyin Zhou ◽  
Yinchun Fan ◽  
Qiang Zhang ◽  
Chengming Xiang ◽  
...  
Keyword(s):  
Poor Prognosis ◽  
Epithelial Mesenchymal Transition ◽  
Malignant Tumors ◽  
Checkpoint Inhibitors ◽  
Enrichment Analysis ◽  
R Package ◽  
High Expression ◽  
Sequencing Data ◽  
Mesenchymal Transition ◽  
Patient Prognosis

Abstract Background Glioblastoma (GBM) is one of the most malignant tumors that can afflict the central nervous system. Previous studies have observed that there are individual differences in the treatment response of immune checkpoint inhibitors in glioblastoma. This study’s aim is to ascertain the factors that may affect the efficacy of immunosuppressant therapy. Methods The clinical data of this study were obtained from a public database. Then, the data was analyzed and processed by R software and corresponding R package. To verify the results of the analysis, information was gathered from 89 GBM patients in our hospital and thereafter the corresponding paraffin sections were stained and quantitatively analyzed by immunohistochemistry. Results From the analysis, it was observed that both CD276 and HAVCR2 were significantly overexpressed in GBM and could be associated with patient prognosis. The analysis of single cell RNA sequencing data and GBM data analysis found an immune subtype with poor prognosis. Further analysis found that the high expression of CD276, HAVCR2 and CD163 was closely related to epithelial-mesenchymal transition (EMT) and could affect the patient prognosis of PD-L1 high expression. GSVA enrichment analysis showed that CD276, HAVCR2 and CD163 might induce EMT by JAK-STAT3 signaling pathway, and RUNX1 and IKZF1 might be transcription factors that regulate CD276/HAVCR2 high expression. Conclusions We found an immune subtype with poor prognosis of GBM, the high expression of CD276, HAVCR2 and CD163 with EMT are closely related and may be one of the factors affecting the efficacy of Anti-PD-L1.

scholarly journals Characterization of the Clinical Significance of PD-1/PD-Ls Expression and Methylation in Patients With Low-Grade Glioma

2021 ◽  
Vol 20 ◽  
pp. 153303382110119
Author(s):  
Jie Mei ◽  
Yun Cai ◽  
Rui Xu ◽  
Xuejing Yang ◽  
Weijian Zhou ◽  
...  
Keyword(s):  
Survival Data ◽  
Immune Escape ◽  
Checkpoint Inhibitors ◽  
Expression Patterns ◽  
Low Grade Glioma ◽  
The Cancer Genome Atlas ◽  
Immune Checkpoints ◽  
Low Grade ◽  
Programmed Death ◽  
Genome Atlas

Background: Immune checkpoints play crucial roles in the immune escape of cancer cells. However, the exact prognostic values of expression and methylation of programmed-death 1 (PD-1), programmed-death-ligand 1 (PD-L1) and PD-L2 in low-grade glioma (LGG) have not been well-defined yet. Methods: A total 514 LGG samples from the Cancer Genome Atlas (TCGA) dataset containing gene expression, DNA methylation, and survival data were enrolled in our study. Besides, a total of 137 primary LGG samples from the Chinese Glioma Genome Atlas (CGGA) database were also extracted for the survival analysis of the prognostic values of PD-1/PD-Ls expression. Results: PD-1/PD-Ls had distinct co-expression patterns in LGG tissues. The expression and methylation level of PD-1/PD-Ls seemed to be various in different LGG subtypes. Besides, overexpression and hypo-methylation of PD-1/PD-Ls were associated with worse prognosis. In addition, PD-1/PD-Ls expression was positively associated with TIICs infiltration, while their methylation was negatively associated with TIICs infiltration. Moreover, PD-1/PD-Ls and their positively correlated gene mainly participated in immune response related biological processes. Conclusion: To conclude, overexpression and hypo-methylation of PD-1/PD-Ls predicted unfavorable prognosis in LGG patients, suggesting those patients may benefit from PD1/PD-Ls checkpoint inhibitors treatment.

scholarly journals Predictive biomarkers of inhibitors immune checkpoints therapy in malignant tumors

2021 ◽  
Vol 8 (2) ◽  
pp. 73-83
Author(s):  
M. V. Kiselevsky ◽  
I. V. Samoylenko ◽  
O. V. Zharkova ◽  
N. V. Ziganshina ◽  
A. A. Petkevich ◽  
...  
Keyword(s):  
Malignant Tumors ◽  
Checkpoint Inhibitors ◽  
Death Receptor ◽  
Predictive Biomarkers ◽  
Peripheral Blood Lymphocytes ◽  
Immune Checkpoints ◽  
Russian Science ◽  
Programmed Death ◽  
Number Of Patients ◽  
Russian Science Citation Index

Immune checkpoint inhibitors (ICT) therapy is a successful immunotherapy (IT) strategy that is quite effective in a number of patients with non-small cell lung cancer, melanoma, bladder cancer, breast cancer and others. Nevertheless, there is a need in predictive markers for ICT therapy for personalized IT as far as there is a large group of patients, the proportion of which varies depending on the tumor, who do not have a clinical response to such therapy. The review summarizes the theoretical aspects and results of clinical trials dedicated to various clinical efficiency predictor using modern databases. As a result of the analysis it is established that the main candidates for the role of such markers are tumor infiltrating lymphocytes and their subpopulations, peripheral blood lymphocytes (PBL) and their subpopulations. PD1 (programmed death receptor 1) and PDL1 (programmed death receptor ligand 1) expression in tumor tissue can also be important for predicting IT efficiency. The most promising predictive biomarker meaning the most clinically relevant is a combination of the PBL subpopulations study and PD1 and PDL1 expression on the tumor cells.PubMed, Scopus, Web of Science, eLibrary, Russian Science Citation Index databases were searched for the available appropriate literature reports. The authors included 82 in the given review.

scholarly journals BOP1 Used as a Novel Prognostic Marker and Correlated with Tumor Microenvironment in Pan-Cancer

2021 ◽  
Vol 2021 ◽  
pp. 1-20
Author(s):  
Wei Li ◽  
Peipei Song ◽  
Mengyuan Zhao ◽  
Lina Gao ◽  
Jianqin Xie ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Tumor Microenvironment ◽  
Cancer Cell ◽  
Prognostic Value ◽  
Malignant Tumors ◽  
Gene Set Enrichment Analysis ◽  
Immune Checkpoints ◽  
Lung Cancer Cell ◽  
Mesenchymal Transition ◽  
Pan Cancer

Previous studies have indicated the important role of block of proliferation 1 (BOP1) in the progression of several malignant tumors; no comprehensive pan-cancer analysis of BOP1 has been performed. Here, we aim to systematically identify the expression, prognostic value, and potential immunological functions of BOP1 in 33 malignancies. We obtained the gene expression data and clinical information from multiple public databases to assess the expression level and prognostic value of BOP1 in 33 cancers. We also analyzed the relationship between BOP1 expression and DNA methylation, tumor microenvironment (TME), microsatellite instability (MSI), tumor mutational burden (TMB), and immune checkpoints. Moreover, we conducted gene set enrichment analysis (GSEA) to investigate the biological function and signal transduction pathways of BOP1 in different types of tumors. Finally, we validated the expression of BOP1 in lung cancer cell line and detected the influence of BOP1 on lung cancer cell migration and the expression of epithelial-mesenchymal transition- (EMT-) related genes. Collectively, our findings elucidated that BOP1 has the potential to be a promising molecular prognostic biomarker for predicting poor survival in various malignant tumors, as well as a cancer-promoting gene involved in tumorigenesis and tumor immunity.

scholarly journals The Role of Matrix Metalloproteinases in the Epithelial-Mesenchymal Transition of Hepatocellular Carcinoma

2019 ◽  
Vol 2019 ◽  
pp. 1-10 ◽  
Author(s):  
Cristian Scheau ◽  
Ioana Anca Badarau ◽  
Raluca Costache ◽  
Constantin Caruntu ◽  
Gratiela Livia Mihai ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Matrix Metalloproteinases ◽  
Epithelial Mesenchymal Transition ◽  
Malignant Tumors ◽  
Transformation Process ◽  
Tissue Inhibitors ◽  
Mesenchymal Transition ◽  
Programmed Death ◽  
Cellular Regeneration

The epithelial-mesenchymal transition (EMT) is a transformation process mandatory for the local and distant progression of many malignant tumors, including hepatocellular carcinoma (HCC). Matrix metalloproteinases (MMPs) play significant roles in cellular regeneration, programmed death, angiogenesis, and many other essential tissular functions, involved in the normal development and also in pathological processes, such as the EMT. This paper reviews the roles of MMPs in the EMT involved in HCC invasion, as well as the ancillary roles that MMP cross-activation and tissue inhibitors play in modulating this process. While gelatinases MMP-2 and MMP-9 are the MMPs commonly cited in the EMT of HCC, MMPs belonging to other classes have been proven to be involved in this process, favoring not only invasion and metastasis (MMP-1, MMP-3, MMP-7, MMP-10, MMP-11, MMP-13, MMP-14, MMP-16, MMP-26, and MMP-28) but also angiogenesis (MMP-8 and MMP-10). There is also data suggesting that other MMPs with a suspected or demonstrated role in the EMT of other cancers may also have some degree of involvement in HCC. The auto- and cross-activation of MMPs may complicate this issue, as pinpointing the extent of implication of each MMP may be extremely difficult. The homeostasis between MMPs and their tissue inhibitors is essential in preventing tumor progression, and the disturbance of this stability is another entailed factor in the EMT of HCC, which is addressed herein.

scholarly journals Current trends in the immunotherapy of metastatic and recurrent squamous cell carcinoma of the head and neck

2020 ◽  
Vol 10 (3) ◽  
pp. 41-47
Author(s):  
Yu. V. Kostalanova ◽  
K. A. Ganina ◽  
A. A. Makhonin ◽  
A. G. Gabrielyan
Keyword(s):  
Squamous Cell Carcinoma ◽  
Immune System ◽  
Cell Carcinoma ◽  
Head And Neck ◽  
Squamous Cell ◽  
Malignant Tumors ◽  
Checkpoint Inhibitors ◽  
Immune Checkpoints ◽  
Programmed Death ◽  
Recurrent Squamous Cell Carcinoma

The immune system plays a key role in the development and progression of head and neck squamous cell carcinoma. Understanding the dysregulation and blockage of the immune system of malignant tumors in this location can improve treatment outcomes. A special group is made up of patients who have a widespread process and relapse after chemotherapy with platinum drugs, because they have a very poor prognosis and limitations in the possibilities of further treatment. To date, the most important data relate to drugs acting on the PD-1 (programmed cell death protein 1)/PD-L1 (programmed death ligand 1) immune checkpoints, which are used by the tumor to block the immune system, which have allowed to increase the effectiveness of treatment. The article presents a clinical case demonstrating the effectiveness of the use of checkpoint inhibitors after the use of platinum preparations.

scholarly journals Protocol for a prospective multicenter intervention study (URivo study) assessing biomarkers in patients with previously treated advanced clear cell renal cell carcinoma receiving nivolumab

2019 ◽  
Vol 6 (2) ◽  
pp. 63
Author(s):  
Hideaki Miyake ◽  
Ken-ichi Harada ◽  
Yuto Matsushita ◽  
Nobuyuki Hinata ◽  
Haruhiko Sugimura ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Intervention Study ◽  
Epithelial Mesenchymal Transition ◽  
Malignant Tumors ◽  
Checkpoint Inhibitors ◽  
Gene Copy ◽  
Enzyme Linked Immunosorbent Assay ◽  
Mesenchymal Transition

<p class="abstract"><strong>Background:</strong> In recent years, immune checkpoint inhibitors have been introduced into routine clinical practice for treating patients with a wide variety of malignant tumors, including advanced renal cell carcinoma (aRCC), resulting in the significant improvement of the prognosis of these patients. However, a reliable biomarker prediciting the clinical course in patients receiving nivolumab has not yet been developed; accordingly, the URivo study was planned to investigate the significance of various candidate biomarkers for aRCC patients treated with nivolumab.</p><p class="abstract"><strong>Methods:</strong> This was designed as a prospective multicenter intervention study, and will include a total of 200 aRCC patients who are scheduled to receive nivolumab followed by treatment with either 1 or 2 tyrosine kinase inhibitors (TKIs). Using resected tumor tissues and serum samples prior to the introduction of nivolumab, the following assessments will be conducted: programmed death ligand-1 (PD-L1) and PD-L2 gene copy number gains by fluorescence in situ hybridization, serum concentrations of PD-L1 and PD-L2 by enzyme-linked immunosorbent assay, and expression of several proteins involved in apoptosis, epithelial-mesenchymal transition, signal transduction and immune reaction by immunohistochemical staining. The outcomes of these assays will be evaluated focusing on the association with the response to nivolumab, overall survival, progression-free survival and disease-specific survival.</p><p class="abstract"><strong>Conclusions: </strong>The significance of various types of candidate biomarker, particularly PD-L1 and PD-L2, will be intensively investigated in this study, and this may offer unique information to determine the optimal indication of nivolumab for aRCC patients following the failure of TKIs.</p><p class="abstract"><strong>Trial Registration:</strong> UMIN000030400; registered April 1, 2018.</p>

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