A Tumor-Specific Super-Enhancer Drives Immune Evasion by Guiding Synchronous Expression of PD-L1 and PD-L2

Xu, Yuanpei; Wu, Yingcheng; Zhang, Siliang; Ma, Panpan; Jin, Xinxin; Wang, Zhou; Yao, Min; Zhang, Erhao; Tao, Baorui; Qin, Yongwei; Chen, Hao; Liu, Aifen; Chen, Miaomiao; Xiao, Mingbing; Lu, Cuihua; Mao, Renfang; Fan, Yihui

doi:10.1016/j.celrep.2019.10.093

Cited by 35 publications

(29 citation statements)

References 39 publications

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“…As shown in the figure, the expression on PC-9 cells was relatively much higher than that on MCF-7 cells. Therefore, we used PC-9 cells as model cancer cells expressing PD-L1 molecules (PD-L1 + ) and MCF-7 as those not expressing PD-L1 (PD-L1 − ), which was also consistent with a previous report [ 29 ]. In this study, the intercellular adhesion forces between a PD-L1 + cell and the two T cells (PD-1 high and PD-1 low ) were mainly measured to evaluate the contribution of PD-1/PD-L1 interactions to intercellular adhesion strengths between T cells and cancer cells, and the influence of nivolumab on adhesion strength was evaluated.…”

Section: Resultssupporting

confidence: 78%

Influence of Nivolumab for Intercellular Adhesion Force between a T Cell and a Cancer Cell Evaluated by AFM Force Spectroscopy

Kim

Ishibashi

Iijima

et al. 2020

Sensors

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The influence of nivolumab on intercellular adhesion forces between T cells and cancer cells was evaluated quantitatively using atomic force microscopy (AFM). Two model T cells, one expressing high levels of programmed cell death protein 1 (PD-1) (PD-1high Jurkat) and the other with low PD-1 expression levels (PD-1low Jurkat), were analyzed. In addition, two model cancer cells, one expressing programmed death-ligand 1 (PD-L1) on the cell surface (PC-9, PD-L1+) and the other without PD-L1 (MCF-7, PD-L1−), were also used. A T cell was attached to the apex of the AFM cantilever using a cup-attached AFM chip, and the intercellular adhesion forces were measured. Although PD-1high T cells adhered strongly to PD-L1+ cancer cells, the adhesion force was smaller than that with PD-L1− cancer cells. After the treatment of PD-1high T cells with nivolumab, the adhesion force with PD-L1+ cancer cells increased to a similar level as with PD-L1− cancer cells. These results can be explained by nivolumab influencing the upregulation of the adhesion ability of PD-1high T cells with PD-L1+ cancer cells. These results were obtained by measuring intercellular adhesion forces quantitatively, indicating the usefulness of single-cell AFM analysis.

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Section: Resultssupporting

confidence: 78%

Influence of Nivolumab for Intercellular Adhesion Force between a T Cell and a Cancer Cell Evaluated by AFM Force Spectroscopy

Kim

Ishibashi

Iijima

et al. 2020

Sensors

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“…Also, some reports explored that the change of 9p24.1 could increase the high expression of PD-L1, because of 9q24.1 including many genes such as JAK2 and PDCD1LG2, which were closely related to PD-L1 expression [30]. Meanwhile, the latest research reported that the tumor-specific superenhancer in 9q24.1 could increase the expression of PD-L1 and PD-L2 [31]. So these genes in 9q24.1 were changed by HPV-DNA integration, which may create some kind of effect to affect PD-L1 expression.…”

Section: Discussionmentioning

confidence: 99%

“…(1) Chip Design and Order. We designed the sequencecapture probes according to 20 types of HPV genome (6,11,16,18,31,33,35,39,42,43,44,45,51,52,53,56,58,59, 66, and 68) sequences, and these probes were produced by Agilent Inc., USA. The enrichment chip was also ordered from Agilent Inc., USA.…”

Section: Methodsmentioning

confidence: 99%

Genome-Wide Profiling of Human Papillomavirus DNA Integration into Human Genome and Its Influence on PD-L1 Expression in Chinese Uygur Cervical Cancer Women

Feng

Sen-Yu

Yuan

et al. 2020

Journal of Immunology Research

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Background. The Uygur is the fifth most populous ethnic group in China. Compared to other Chinese population, cervical cancer in them had high incidence, and HPV infection also was particular. Their HPV integration situation has never been reported. We aimed to investigate the integration situation of 20 subtypes of HPV gene into host cell genome in Chinese Uygur cervical cancer patients; meanwhile, we explored the influence of gene integration on PD-L1 expression. Methods. 40 frozen Chinese Uygur cervical cancer specimens with positive HPV infection were obtained from the cancer prevention and treatment institute of Tumor Hospital Affiliated to Xinjiang Medical University. The integration situation of HPV gene into host cell genome was detected by Agilent SureSelect™ Target Enrichment Chip and Next-Generation Sequencing. The related genes were analyzed by GO functional annotation and KEGG pathway enrichment. The expression levels of PD-L1 in cancer cells were tested by immunohistochemical assay (IHC). Meanwhile, the relationship between PD-L1 levels in cancer cells and gene integration were analyzed. Results. The HPV multiple infection rate by HIVID was as high as 92.5%, much higher than 35.0% by the commercial kit (P<0.05). There were 13423 integration events in 40 specimens, involving 6867 human genes. These integration events were distributed on all human chromosomes, and chromosome 19 had the excessive concentration phenomenon of integration events. There were some integration hotspots in human genome such as PPP1R37, HECW2, EMBP1, ANKRD50, SPTBN4, LINC00895, LYRM4-AS1, LINC00374, RBFOX1, CSMD1, CDH13, and KLHL4. Insertion breakpoints can be found in all gene regions of the HPV genome. The actual observation of the integration times of E1 and E6 was much higher than the expected value, while the actual observation times of E5 were much lower than the expected value. The result of GO functional analysis showed that binding molecular function and cellular process biological process were the main ways to influence the cell biological behavior of HPV gene integration. The enrichment pathway analysis of KEGG showed that pathways in cancer were the most important enrichment pathways involved in the genomic integration of HPV. The positive PD-L1 rate was 62.5%. Logistic regression analysis showed that 9p24.1 existing integration sites and the number of all gene integration were risk factors for PD-L1 expression (odds ratio 17.313 and 1.012; 95% confidence interval 1.691-177.213 and 1.001-1.023). Conclusions and Relevance. Most high-frequency sites of HPV integration in Chinese Uygur cervical cancer are related to cancer progression, and the gene integration hotspots may be potential HPV carcinogenic targets. The problem of multiple HPV infection in Chinese Uygur cervical cancer patients should be paid attention. L1 and E6 genes are inapposite as the target gene of commercial HPV type detection kit, because of high-frequency breakpoints in these genes. The gene integration especially the integration existing on 9p24.1 could affect the expression level of PD-L1.

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“…An increase in PD-L1 expression due to 3′-UTR disruption is thought to interfere with post-transcriptional regulation such as miR-mediated control, resulting in a decreased mRNA decay rate [ 80 , 95 , 96 , 97 , 98 ]. A super-enhancer located between the PD-L1 and PD-L2 genes has recently been identified [ 99 ] and shown to maintain expression of PD-L1 independently of IFNγ. It is subject to epigenetic regulation and sensitized cancer cells to PD-1 blockade [ 99 ].…”

Section: Expression Of Pd-l1 By Tumor Cellsmentioning

confidence: 99%

“…A super-enhancer located between the PD-L1 and PD-L2 genes has recently been identified [ 99 ] and shown to maintain expression of PD-L1 independently of IFNγ. It is subject to epigenetic regulation and sensitized cancer cells to PD-1 blockade [ 99 ].…”

Section: Expression Of Pd-l1 By Tumor Cellsmentioning

confidence: 99%

Spatial and Temporal Changes in PD-L1 Expression in Cancer: The Role of Genetic Drivers, Tumor Microenvironment and Resistance to Therapy

Shklovskaya

Rizos

2020

IJMS

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Immunotherapies blocking immune inhibitory receptors programmed cell death-1 (PD-1) and cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) on T-cells have dramatically improved patient outcomes in a range of advanced cancers. However, the lack of response, and the development of resistance remain major obstacles to long-term improvements in patient outcomes. There is significant interest in the clinical use of biomarkers to improve patient selection, and the expression of PD-1 ligand 1 (PD-L1) is often reported as a potential biomarker of response. However, accumulating evidence suggests that the predictive value of PD-L1 expression in tumor biopsies is relatively low due, in part, to its complex biology. In this review, we discuss the biological consequences of PD-L1 expression by various cell types within the tumor microenvironment, and the complex mechanisms that regulate PD-L1 expression at the genomic, transcriptomic and proteomic levels.

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A Tumor-Specific Super-Enhancer Drives Immune Evasion by Guiding Synchronous Expression of PD-L1 and PD-L2

Cited by 35 publications

References 39 publications

Influence of Nivolumab for Intercellular Adhesion Force between a T Cell and a Cancer Cell Evaluated by AFM Force Spectroscopy

Influence of Nivolumab for Intercellular Adhesion Force between a T Cell and a Cancer Cell Evaluated by AFM Force Spectroscopy

Genome-Wide Profiling of Human Papillomavirus DNA Integration into Human Genome and Its Influence on PD-L1 Expression in Chinese Uygur Cervical Cancer Women

Spatial and Temporal Changes in PD-L1 Expression in Cancer: The Role of Genetic Drivers, Tumor Microenvironment and Resistance to Therapy

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