scholarly journals 907 Modulation of tumor immunogenicity by DNA methylation of immune synapse genes in cancers

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A952-A952
Author(s):  
Imene Hamaidi ◽  
Anders Berglund ◽  
Matthew Mills ◽  
Ryan Putney ◽  
James Mule ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Methylation Profile ◽  
Epithelial Cancer ◽  
Immune Synapse ◽  
Adjacent Tissue ◽  
Normal Adjacent Tissue ◽  
Cancer Genome Atlas ◽  
Tumor Immunogenicity ◽  
Checkpoint Genes ◽  
Genome Atlas

BackgroundCancer immunotherapy represents a major paradigm shift in cancer care. Despite such breakthrough, majority of cancer patients remains refractory to existing immunotherapeutic modalities highlighting the inherent capacity of tumors to escape immunosurveillance mechanisms. Frequently, cancer cells utilize the epigenetic machinery to silence tumor suppressors or activate oncogenes for survival and proliferation. Likewise, tumor cells might employ the epigenetic reprogramming of immune-related pathways to evade the immune system. Methylation is one of the major epigenetic mechanisms modulating gene transcription. Thus, we investigated the methylation profile of both co-stimulatory and immune checkpoint genes in cancer.MethodsData from The Cancer Genome Atlas (TCGA) were used for methylation profiling and RNA-sequencing analysis. Twenty-six epithelial cancer cell lines with more than 3 mock and three 5-azacitidine–treated samples were selected for analysis from the GSE57342 dataset. t-distributed stochastic neighbor embedding (t-SNE) was calculated using 247 probes for the selected 20 genes across all TCGA samples. t-SNE analysis was performed on 8,186 solid tumors and 745 normal adjacent tissues for methylation levels for all probes. For principal component analysis, first and second principal components were used to represent the overall methylation status for 8,931 tumor and normal samples in the TCGA database. Survival analyses were retrieved from a prior publication.1ResultsWe found that methylation profile of immune synapse genes is distinct in tumor versus normal adjacent tissue. Interestingly, our results demonstrate hypermethylation of co-stimulatory genes such as CD40 and hypo-methylation of immune checkpoint genes such as HHLA2 and PDL1 across multiple tumor types in comparison with the normal adjacent tissue. In addition, an inverse correlation between methylation and gene expression was manifest among tumor and normal adjacent tissue, confirming the epigenetic mechanism of gene suppression by gene methylation. Furthermore, we observed a reversal of hypermethylation of the co-stimulatory genes including CD40 by the demethylating agent 5-azacytidine in the data set of 26 epithelial cancer cell lines. Finally, we found that that hypomethylation of co-stimulatory genes within the immune synapse correlates with functional T cell recruitment to the tumor microenvironment and is followed by a favorable clinical outcome in melanoma patients.ConclusionsOur finding unveils methylation of immune synapse genes as a crucial driver of the immune evasive phenotype of cancer cells. Notably, identification of actionable targets to restore tumor immunogenicity is an attractive strategy in combination with immune checkpoint blockade.AcknowledgementsThis work was supported by NIH grant K08 CA194273, the Immunology Innovation Fund, an NCI Cancer Center Support grant, (P30-CA076292), the Miriam and Sheldon G. Adelson Foundation, and the Moffitt Foundation.ReferenceLiu J, Lichtenberg T, Hoadley KA, Poisson LM, Lazar AJ, Cherniack AD, Kovatich AJ, Benz CC, Levine DA, Lee AV, Omberg L, Wolf DM, Shriver CD, Thorsson V, Cancer Genome Atlas Research N, Hu H. An integrated TCGA pan-cancer clinical data resource to drive high-quality survival outcome analytics. Cell 2018;173(2):400–16 e11.

scholarly journals The PD-L1 Metabolic Interactome Intersects with Choline Metabolism and Inflammation

2020 ◽  
Author(s):  
Jesús Pacheco-Torres ◽  
Marie-France Penet ◽  
Yelena Mironchik ◽  
Balaji Krishnamachary ◽  
Zaver M Bhujwalla
Keyword(s):  
Breast Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Immune Checkpoint ◽  
Cancer Metabolism ◽  
The Cancer Genome Atlas ◽  
Immune Checkpoints ◽  
Cancer Genome Atlas ◽  
Cox 2 ◽  
Genome Atlas

Abstract Background: Harnessing the power of the immune system by using immune checkpoint inhibitors has resulted in some of the most exciting advances in cancer treatment. The full potential of this approach has, however, not been fully realized for treating many cancers such as pancreatic and breast cancer. Cancer metabolism influences many aspects of cancer progression including immune surveillance. An expanded understanding of how cancer metabolism can directly impact immune checkpoints may allow further optimization of immunotherapy. We therefore investigated, for the first time, the relationship between the overexpression of choline kinase-α (Chk-α), an enzyme observed in most cancers, and expression of the immune checkpoint PD-L1. Methods: We used small interfering RNA to downregulate Chk-a, PD-L1 or both in two triple negative human breast cancer cell lines (MDA-MB-231 and SUM-149) and two human pancreatic ductal adenocarcinoma cell lines (Pa09C and Pa20C). The effects of the downregulation were studied at the genomic, proteomic and metabolomic levels. The findings were compared with results obtained by analysis of public data from The Cancer Genome Atlas Program.Results: We identified an inverse dependence between Chk-α and PD-L1 at the genomic, proteomic and metabolomic levels. We also found that prostaglandin-endoperoxide synthase 2 (COX-2) and transforming growth factor beta (TGF-β) play an important role in this relationship. We independently confirmed this relationship in human cancers by analyzing data from The Cancer Genome Atlas Program. Conclusions: Our data identified previously unknown roles of PD-L1 in cancer cell metabolic reprogramming, and revealed the immunosuppressive increased PD-L1 effect of Chk-α downregulation. These data suggest that PD-L1 regulation of metabolism may be mediated through Chk-α, COX-2 and TGF-β. The observations provide new insights that can be applied to the rational design of combinatorial therapies targeting immune checkpoints and cancer metabolism.

scholarly journals The PD-L1 metabolic interactome intersects with choline metabolism and inflammation

2021 ◽  
Author(s):  
Jesús Pacheco-Torres ◽  
Marie-France Penet ◽  
Yelena Mironchik ◽  
Balaji Krishnamachary ◽  
Zaver M Bhujwalla
Keyword(s):  
Breast Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Immune Checkpoint ◽  
Cancer Metabolism ◽  
The Cancer Genome Atlas ◽  
Immune Checkpoints ◽  
Cancer Genome Atlas ◽  
Cox 2 ◽  
Genome Atlas

Abstract Background: Harnessing the power of the immune system by using immune checkpoint inhibitors has resulted in some of the most exciting advances in cancer treatment. The full potential of this approach has, however, not been fully realized for treating many cancers such as pancreatic and breast cancer. Cancer metabolism influences many aspects of cancer progression including immune surveillance. An expanded understanding of how cancer metabolism can directly impact immune checkpoints may allow further optimization of immunotherapy. We therefore investigated, for the first time, the relationship between the overexpression of choline kinase-α (Chk-α), an enzyme observed in most cancers, and expression of the immune checkpoint PD-L1. Methods: We used small interfering RNA to downregulate Chk-a, PD-L1 or both in two triple negative human breast cancer cell lines (MDA-MB-231 and SUM-149) and two human pancreatic ductal adenocarcinoma cell lines (Pa09C and Pa20C). The effects of the downregulation were studied at the genomic, proteomic and metabolomic levels. The findings were compared with results obtained by analysis of public data from The Cancer Genome Atlas Program.Results: We identified an inverse dependence between Chk-α and PD-L1 at the genomic, proteomic and metabolomic levels. We also found that prostaglandin-endoperoxide synthase 2 (COX-2) and transforming growth factor beta (TGF-β) play an important role in this relationship. We independently confirmed this relationship in human cancers by analyzing data from The Cancer Genome Atlas Program. Conclusions: Our data identified previously unknown roles of PD-L1 in cancer cell metabolic reprogramming, and revealed the immunosuppressive increased PD-L1 effect of Chk-α downregulation. These data suggest that PD-L1 regulation of metabolism may be mediated through Chk-α, COX-2 and TGF-β. The observations provide new insights that can be applied to the rational design of combinatorial therapies targeting immune checkpoints and cancer metabolism.

scholarly journals The PD-L1 metabolic interactome intersects with choline metabolism and inflammation

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Jesus Pacheco-Torres ◽  
Marie-France Penet ◽  
Yelena Mironchik ◽  
Balaji Krishnamachary ◽  
Zaver M. Bhujwalla
Keyword(s):  
Breast Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Immune Checkpoint ◽  
Cancer Metabolism ◽  
The Cancer Genome Atlas ◽  
Immune Checkpoints ◽  
Cancer Genome Atlas ◽  
Cox 2 ◽  
Genome Atlas

Abstract Background Harnessing the power of the immune system by using immune checkpoint inhibitors has resulted in some of the most exciting advances in cancer treatment. The full potential of this approach has, however, not been fully realized for treating many cancers such as pancreatic and breast cancer. Cancer metabolism influences many aspects of cancer progression including immune surveillance. An expanded understanding of how cancer metabolism can directly impact immune checkpoints may allow further optimization of immunotherapy. We therefore investigated, for the first time, the relationship between the overexpression of choline kinase-α (Chk-α), an enzyme observed in most cancers, and the expression of the immune checkpoint PD-L1. Methods We used small interfering RNA to downregulate Chk-α, PD-L1, or both in two triple-negative human breast cancer cell lines (MDA-MB-231 and SUM-149) and two human pancreatic ductal adenocarcinoma cell lines (Pa09C and Pa20C). The effects of the downregulation were studied at the genomic, proteomic, and metabolomic levels. The findings were compared with the results obtained by the analysis of public data from The Cancer Genome Atlas Program. Results We identified an inverse dependence between Chk-α and PD-L1 at the genomic, proteomic, and metabolomic levels. We also found that prostaglandin-endoperoxide synthase 2 (COX-2) and transforming growth factor beta (TGF-β) play an important role in this relationship. We independently confirmed this relationship in human cancers by analyzing data from The Cancer Genome Atlas Program. Conclusions Our data identified previously unknown roles of PD-L1 in cancer cell metabolic reprogramming, and revealed the immunosuppressive increased PD-L1 effect of Chk-α downregulation. These data suggest that PD-L1 regulation of metabolism may be mediated through Chk-α, COX-2, and TGF-β. The observations provide new insights that can be applied to the rational design of combinatorial therapies targeting immune checkpoints and cancer metabolism.

scholarly journals Identifying a Clinically Applicable Mutational Burden Threshold as a Potential Biomarker of Response to Immune Checkpoint Therapy in Solid Tumors

2017 ◽  
pp. 1-13 ◽  
Author(s):  
Anshuman Panda ◽  
Anil Betigeri ◽  
Kalyanasundaram Subramanian ◽  
Jeffrey S. Ross ◽  
Dean C. Pavlick ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Immune Checkpoint ◽  
Immune Checkpoint Blockade ◽  
The Cancer Genome Atlas ◽  
Checkpoint Activation ◽  
Mutational Burden ◽  
Whole Exome ◽  
Cancer Genome Atlas ◽  
Cancer Types ◽  
Genome Atlas

Purpose An association between mutational burden and response to immune checkpoint therapy has been documented in several cancer types. The potential for such a mutational burden threshold to predict response to immune checkpoint therapy was evaluated in several clinical datasets, where mutational burden was measured either by whole-exome sequencing or by using commercially available sequencing panels. Methods Whole-exome sequencing and RNA sequencing data of 33 solid cancer types from The Cancer Genome Atlas were analyzed to determine whether a robust immune checkpoint–activating mutation (iCAM) burden threshold associated with evidence of immune checkpoint activation exists in these cancers that may serve as a biomarker of response to immune checkpoint blockade therapy. Results We found that a robust iCAM threshold, associated with signatures of immune checkpoint activation, exists in eight of 33 solid cancers: melanoma, lung adenocarcinoma, colon adenocarcinoma, endometrial cancer, stomach adenocarcinoma, cervical cancer, estrogen receptor–positive/human epidermal growth factor receptor 2–negative breast cancer, and bladder-urothelial cancer. Tumors with a mutational burden higher than the threshold (iCAM positive) also had clear histologic evidence of lymphocytic infiltration. In published datasets of melanoma, lung adenocarcinoma, and colon cancer, patients with iCAM-positive tumors had significantly better response to immune checkpoint therapy compared with those with iCAM-negative tumors. Receiver operating characteristic analysis using The Cancer Genome Atlas predictions as the gold standard showed that iCAM-positive tumors are accurately identifiable using clinical sequencing assays, such as FoundationOne (Foundation Medicine, Cambridge, MA) or StrandAdvantage (Strand Life Sciences, Bangalore, India). Using the FoundationOne-derived threshold, an analysis of 113 melanoma tumors showed that patients with iCAM-positive disease have significantly better response to immune checkpoint therapy. iCAM-positive and iCAM-negative tumors have distinct mutation patterns and different immune microenvironments. Conclusion In eight solid cancers, a mutational burden threshold exists that may predict response to immune checkpoint blockade. This threshold is identifiable using available clinical sequencing assays.

Comprehensive assessment of PD-L1 and PD-L2 dysregulation in gastrointestinal cancers

Epigenomics ◽  
2020 ◽  
Author(s):  
Qijie Zhao ◽  
Jinan Guo ◽  
Yueshui Zhao ◽  
Jing Shen ◽  
Parham Jabbarzadeh Kaboli ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Signaling Pathways ◽  
Underlying Mechanism ◽  
Comprehensive Analysis ◽  
The Cancer Genome Atlas ◽  
Gastrointestinal Cancers ◽  
Tumor Mutation Burden ◽  
Mutation Burden ◽  
Cancer Genome Atlas ◽  
Genome Atlas

Background: PD-L1 and PD-L2 are ligands of PD-1. Their overexpression has been reported in different cancers. However, the underlying mechanism of PD-L1 and PD-L2 dysregulation and their related signaling pathways are still unclear in gastrointestinal cancers. Materials & methods: The expression of PD-L1 and PD-L2 were studied in The Cancer Genome Atlas and Genotype-Tissue Expression databases. The gene and protein alteration of PD-L1 and PD-L2 were analyzed in cBioportal. The direct transcription factor regulating PD-L1/ PD-L2 was determined with ChIP-seq data. The association of PD-L1/PD-L2 expression with clinicopathological parameters, survival, immune infiltration and tumor mutation burden were investigated with data from The Cancer Genome Atlas. Potential targets and pathways of PD-L1 and PD-L2 were determined by protein enrichment, WebGestalt and gene ontology. Results: Comprehensive analysis revealed that PD-L1 and PD-L2 were significantly upregulated in most types of gastrointestinal cancers and their expressions were positively correlated. SP1 was a key transcription factor regulating the expression of PD-L1. Conclusion: Higher PD-L1 or PD-L2 expression was significantly associated with poor overall survival, higher tumor mutation burden and more immune and stromal cell populations. Finally, HIF-1, ERBB and mTOR signaling pathways were most significantly affected by PD-L1 and PD-L2 dysregulation. Altogether, this study provided comprehensive analysis of the dysregulation of PD-L1 and PD-L2, its underlying mechanism and downstream pathways, which add to the knowledge of manipulating PD-L1/PD-L2 for cancer immunotherapy.

scholarly journals RUNX1 and REXO2 are associated with the heterogeneity and prognosis of IDH wild type lower grade glioma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Haiwei Wang ◽  
Xinrui Wang ◽  
Liangpu Xu ◽  
Ji Zhang ◽  
Hua Cao
Keyword(s):  
Transcription Factor ◽  
Low Frequency ◽  
Tumor Grade ◽  
The Cancer Genome Atlas ◽  
Lower Grade ◽  
Wild Type ◽  
Lower Grade Glioma ◽  
Cancer Genome Atlas ◽  
Worse Prognosis ◽  
Genome Atlas

AbstractBased on isocitrate dehydrogenase (IDH) alterations, lower grade glioma (LGG) is divided into IDH mutant and wild type subgroups. However, the further classification of IDH wild type LGG was unclear. Here, IDH wild type LGG patients in The Cancer Genome Atlas and Chinese Glioma Genome Atlas were divided into two sub-clusters using non-negative matrix factorization. IDH wild type LGG patients in sub-cluster2 had prolonged overall survival and low frequency of CDKN2A alterations and low immune infiltrations. Differentially expressed genes in sub-cluster1 were positively correlated with RUNX1 transcription factor. Moreover, IDH wild type LGG patients with higher stromal score or immune score were positively correlated with RUNX1 transcription factor. RUNX1 and its target gene REXO2 were up-regulated in sub-cluster1 and associated with the worse prognosis of IDH wild type LGG. RUNX1 and REXO2 were associated with the higher immune infiltrations. Furthermore, RUNX1 and REXO2 were correlated with the worse prognosis of LGG or glioma. IDH wild type LGG in sub-cluster2 was hyper-methylated. REXO2 hyper-methylation was associated with the favorable prognosis of LGG or glioma. At last, we showed that, age, tumor grade and REXO2 expression were independent prognostic factors in IDH wild type LGG.

Sign in / Sign up

Export Citation Format

Share Document