scholarly journals Identification of tumor antigens and immune subtypes in lower grade gliomas for mRNA vaccine development

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Liguo Ye ◽  
Long Wang ◽  
Ji’an Yang ◽  
Ping Hu ◽  
Chunyu Zhang ◽  
...  
Keyword(s):  
Tumor Antigens ◽  
Vaccine Development ◽  
Enrichment Analysis ◽  
Normal Brain ◽  
Lower Grade ◽  
Tumor Vaccines ◽  
Cancer Vaccination ◽  
Differential Expression Gene ◽  
Mutation Burden ◽  
Immune Related Genes

Abstract Background As an important part of tumor immunotherapy for adjunct, therapeutic tumor vaccines have been effective against multiple solid cancers, while their efficacy against lower grade glioma (LGG) remains undefined. Immunophenotyping of tumors is an essential tool to evaluate the immune function of patients with immunodeficiency or autoimmunity. Therefore, this study aims to find the potential tumor antigen of LGG and identify the suitable population for cancer vaccination based on the immune landscape. Method The genomic and clinical data of 529 patients with LGG were obtained from TCGA, the mRNA_seq data of normal brain tissue were downloaded from GTEx. Differential expression gene and mutation analysis were performed to screen out potential antigens, K-M curves were carried out to investigate the correlation between the level of potential antigens and OS and DFS of patients. TIMER dataset was used to explore the correlation between genes and immune infiltrating cells. Immunophenotyping of 529 tumor samples was based on the single-sample gene sets enrichment analysis. Cibersort and Estimate algorithm were used to explore the tumor immune microenvironment characteristics in each immune subtype. Weighted gene co-expression network analysis (WGCNA) clustered immune-related genes and screened the hub genes, and pathway enrichment analyses were performed on the hub modules related to immune subtype in the WGCNA. Results Selecting for the mutated, up-regulated, prognosis- and immune-related genes, four potential tumor antigens were identified in LGG. They were also significantly positively associated with the antigen-presenting immune cells (APCs). Three robust immune subtypes, IS1, IS2 and IS3, represented immune status "desert", "immune inhibition", and "inflamed" respectively, which might serve as a predictive parameter. Subsequently, clinicopathological features, including the codeletion status of 1p19q, IDH mutation status, tumor mutation burden, tumor stemness, etc., were significantly different among subtypes. Conclusion FCGBP, FLNC, TLR7, and CSF2RA were potential antigens for developing cancer vaccination, and the patients in IS3 were considered the most suitable for vaccination in LGG.

scholarly journals Identification of Tumor Antigens and Immune Landscape in Glioblastoma for mRNA Vaccine Development

2021 ◽  
Vol 12 ◽  
Author(s):  
Liguo Ye ◽  
Long Wang ◽  
Ji’an Yang ◽  
Ping Hu ◽  
Chunyu Zhang ◽  
...  
Keyword(s):  
Immune Cells ◽  
Tumor Antigens ◽  
Vaccine Development ◽  
Enrichment Analysis ◽  
Copy Number Variant ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Normal Brain ◽  
Consensus Clustering ◽  
Tumor Vaccines

Background: Clinical benefits from standard therapies against glioblastoma (GBM) are limited in part due to the intrinsic radio- and chemo-resistance. As an essential part of tumor immunotherapy for adjunct, therapeutic tumor vaccines have been effective against multiple solid cancers, while their efficacy against GBM remains undefined. Therefore, this study aims to find the possible tumor antigens of GBM and identify the suitable population for cancer vaccination through immunophenotyping.Method: The genomic and responding clinical data of 169 GBM samples and five normal brain samples were obtained from The Cancer Genome Atlas (TCGA). The mRNA_seq data of 940 normal brain tissue were downloaded from Genotype-Tissue Expression (GTEx). Potential GBM mRNA antigens were screened out by differential expression, copy number variant (CNV), and mutation analysis. K-M survival and Cox analysis were carried out to investigate the prognostic association of potential tumor antigens. Tumor Immune Estimation Resource (TIMER) was used to explore the association between the antigens and tumor immune infiltrating cells (TIICs). Immunophenotyping of 169 samples was performed through consensus clustering based on the abundance of 22 kinds of immune cells. The characteristics of the tumor immune microenvironment (TIME) in each cluster were explored through single-sample gene set enrichment analysis based on 29 kinds of immune-related hallmarks and pathways. Weighted gene co-expression network analysis (WGCNA) was performed to cluster the genes related to immune subtypes. Finally, pathway enrichment analyses were performed to annotate the potential function of modules screened through WGCNA.Results: Two potential tumor antigens selected were significantly positively associated with the antigen-presenting immune cells (APCs) in GBM. Furthermore, the expression of antigens was verified at the protein level by Immunohistochemistry. Two robust immune subtypes, immune subtype 1 (IS1) and immune subtype 2 (IS2), representing immune status “immune inhibition” and “immune inflamed”, respectively, had distinct clinical outcomes in GBM.Conclusion: ARPC1B and HK3 were potential mRNA antigens for developing GBM mRNA vaccination, and the patients in IS2 were considered the most suitable population for vaccination in GBM.

scholarly journals Validation of the Functions and Prognostic Values of Synapse Associated Proteins in Lower-grade Glioma

2021 ◽  
Author(s):  
Han Lin ◽  
Yong Yang ◽  
Chongxian Hou ◽  
Yuqing Huang ◽  
Liting Zhou ◽  
...  
Keyword(s):  
Synapse Formation ◽  
Enrichment Analysis ◽  
Normal Brain ◽  
Lower Grade ◽  
Protein Protein Interaction ◽  
Reverse Transcription Pcr ◽  
Function Enrichment Analysis ◽  
Associated Proteins ◽  
Clinicopathological Significance ◽  
Novel Strategy

Synapse and synapse associated proteins (SAPs) play critical roles in various neurodegeneration diseases and brain tumors. However, in lower-grade gliomas (LGG), SAPs have not been explored systematically. Herein, we are going to explore SAPs expression profile and its clinicopathological significance in LGG which can offer new insights to glioma therapy. In this study, we integrate a list of SAPs that covered 231 proteins with synaptogenesis activity and post synapse formation. The LGG RNA-seq data were downloaded from GEO, TCGA and CGGA database. The prognosis associated SAPs in key modules of PPI (protein-protein interaction networks) was regarded as hub SAPs. Western blot, quantitative reverse transcription PCR (qRT-PCR) and immunochemistry results from HPA database were used to verify the expression of hub SAPs. There were 68 upregulated SAPs and 44 downregulated SAPs in LGG tissue compared with normal brain tissue. Data from function enrichment analysis revealed functions of differentially expressed SAPs in synapse organization and glutamatergic receptor pathway in LGGs. Survival analysis revealed that four SAPs, GRIK2, GABRD, GRID2 and ARC were correlate with the prognosis of LGG patients. Interestingly, we found that GABRD were upregulated in LGG patients with seizures, indicating that SAPs may link to the pathogenesis of seizures in glioma patients. The four-SAPs signature was revealed as an independent prognostic factor in gliomas. Our study presented a novel strategy to assess the prognostic risks of LGGs, based on the expression of SAPs.

scholarly journals Identification of tumor antigens and immune subtypes of pancreatic adenocarcinoma for mRNA vaccine development

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Xing Huang ◽  
Gang Zhang ◽  
Tianyu Tang ◽  
Tingbo Liang
Keyword(s):  
Pancreatic Adenocarcinoma ◽  
Tumor Antigens ◽  
Vaccine Development ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Clinical Information ◽  
Genetic Alterations ◽  
Immune Checkpoints ◽  
Immune Gene ◽  
Mutation Burden

Abstract Background Although mRNA vaccines have been effective against multiple cancers, their efficacy against pancreatic adenocarcinoma (PAAD) remains undefined. Accumulating evidence suggests that immunotyping can indicate the comprehensive immune status in tumors and their immune microenvironment, which is closely associated with therapeutic response and vaccination potential. The aim of this study was to identify potent antigens in PAAD for mRNA vaccine development, and further distinguish immune subtypes of PAAD to construct an immune landscape for selecting suitable patients for vaccination. Methods Gene expression profiles and clinical information of 239 PAAD datasets were extracted from ICGC, and RNA-Seq data of 103 samples were retrieved from TCGA. GEPIA was used to calculate differential expression levels and prognostic indices, cBioPortal program was used to compare genetic alterations, and TIMER was used to explore correlation between genes and immune infiltrating cells. Consensus cluster was used for consistency matrix construction and data clustering, DAVID was used for functional annotation, and graph learning-based dimensional reduction was used to depict immune landscape. Results Six overexpressed and mutated tumor antigens associated with poor prognosis and infiltration of antigen presenting cells were identified in PAAD, including ADAM9, EFNB2, MET, TMOD3, TPX2, and WNT7A. Furthermore, five immune subtypes (IS1-IS5) and nine immune gene modules of PAAD were identified that were consistent in both patient cohorts. The immune subtypes showed distinct molecular, cellular and clinical characteristics. IS1 and IS2 exhibited immune-activated phenotypes and correlated to better survival compared to the other subtypes. IS4 and IS5 tumors were immunologically cold and associated with higher tumor mutation burden. Immunogenic cell death modulators, immune checkpoints, and CA125 and CA199, were also differentially expressed among the five immune subtypes. Finally, the immune landscape of PAAD showed a high degree of heterogeneity between individual patients. Conclusions ADAM9, EFNB2, MET, TMOD3, TPX2, and WNT7A are potent antigens for developing anti-PAAD mRNA vaccine, and patients with IS4 and IS5 tumors are suitable for vaccination.

scholarly journals Validation of the Functions and Prognostic Values of Synapse Associated Proteins in Lower-Grade Glioma

2020 ◽  
Author(s):  
Han Lin ◽  
Yong Yang ◽  
Chongxian Hou ◽  
Jiantao Zheng ◽  
Guangzhao Lv ◽  
...  
Keyword(s):  
Survival Analysis ◽  
Prognostic Significance ◽  
Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Differentially Expressed ◽  
Prognostic Models ◽  
Normal Brain ◽  
Lower Grade ◽  
Associated Proteins ◽  
Genome Atlas

Abstract BackgroundSynapse and synapse associated proteins (SAPs) play critical roles in various neurodegeneration diseases and brain tumors. However, in lower-grade gliomas (LGG), SAPs have not been explored systematically. Herein, we are going to explore SAPs expression profile and its clinicopathological significance in LGG which can offer new insights to glioma therapy. MethodIn this study, we used five sources including, Venkatesh, Shen, Colón, Jüttner R, Gene Ontology (GO) project to integrate a list of SAPs that covered 231 proteins with synaptogenesis activity and post synapse formation. The LGG RNA-seq data were downloaded from gene expression omnibus (GEO) database, The Cancer Genome Atlas (TCGA), and Chinese Glioma Genome Atlas (CGGA). The differentially expressed SAPs were filtered out and constructed PPI to search for key modules and SAPs. Then, using Kaplan–Meier survival analysis, least absolute shrinkage and selection operator (LASSO), and multicox regression analysis, the prognostic significance of these key SAPs was evaluated. CGGA database, Human Protein Altas (HPA) and quantitative real-time PCR were used to verify our findings. ResultData from function enrichment analysis revealed functions of differentially expressed SAPs in synapse organization and glutamatergic receptor pathway in LGGs. Survival analysis revealed four SAPs, GRIK2, GABRD, GRID2, ARC that were correlate with the prognosis of LGG patients and used to construct the prognostic models. Among them, the expression of GABRD was lower in glioma tissue than normal brain tissue, but higher in seizure LGG patients than non-seizure patients. The four-SAPs signature was revealed as an independent prognostic factor in gliomas. ConclusionOur study presented a novel strategy to assess the prognostic risks of LGGs, based on the expression of SAPs. Also, we revealed that several SAPs upregulated in patients with seizures, indicating that they are linked to the pathogenesis of seizures in glioma patients.

scholarly journals Validation of the Functions and Prognostic Values of Synapse Associated Proteins in Lower-Grade Glioma

2020 ◽  
Author(s):  
Han Lin ◽  
Yong Yang ◽  
Chongxian Hou ◽  
Jiantao Zheng ◽  
Guangzhao Lv ◽  
...  
Keyword(s):  
Survival Analysis ◽  
Prognostic Significance ◽  
Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Differentially Expressed ◽  
Prognostic Models ◽  
Normal Brain ◽  
Lower Grade ◽  
Associated Proteins ◽  
Genome Atlas

Abstract Background: Synapse and synapse associated proteins (SAPs) play critical roles in various neurodegeneration diseases and brain tumors. However, in lower-grade gliomas (LGG), SAPs have not been explored systematically. Herein, we are going to explore SAPs expression profile and its clinicopathological significance in LGG which can offer new insights to glioma therapy. Method: In this study, we used five sources including, Venkatesh, Shen, Colón, Jüttner R, Gene Ontology (GO) project to integrate a list of SAPs that covered 231 proteins with synaptogenesis activity and post synapse formation. The LGG RNA-seq data were downloaded from gene expression omnibus (GEO) database, The Cancer Genome Atlas (TCGA), and Chinese Glioma Genome Atlas (CGGA). The differentially expressed SAPs were filtered out and constructed PPI to search for key modules and SAPs. Then, using Kaplan–Meier survival analysis, least absolute shrinkage and selection operator (LASSO), and multicox regression analysis, the prognostic significance of these key SAPs was evaluated. CGGA database, Human Protein Altas (HPA) and quantitative real-time PCR were used to verify our findings. Result: Data from function enrichment analysis revealed functions of differentially expressed SAPs in synapse organization and glutamatergic receptor pathway in LGGs. Survival analysis revealed four SAPs, GRIK2, GABRD, GRID2, ARC that were correlate with the prognosis of LGG patients and used to construct the prognostic models. Among them, the expression of GABRD was lower in glioma tissue than normal brain tissue, but higher in seizure LGG patients than non-seizure patients. The four-SAPs signature was revealed as an independent prognostic factor in gliomas.Conclusion: Our study presented a novel strategy to assess the prognostic risks of LGGs, based on the expression of SAPs. Also, we revealed that several SAPs upregulated in patients with seizures, indicating that they are linked to the pathogenesis of seizures in glioma patients.

scholarly journals Autologous tumor antigens and boron nanosheet-based nanovaccines for enhanced photo-immunotherapy against immune desert tumors

Nanophotonics ◽  
2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Zhe Sun ◽  
Taojian Fan ◽  
Quan Liu ◽  
Luodan Huang ◽  
Weibin Hu ◽  
...  
Keyword(s):  
Immune Cells ◽  
Tumor Antigens ◽  
Photoacoustic Imaging ◽  
Metastatic Potential ◽  
Photothermal Effect ◽  
Patient Specific ◽  
Autologous Tumor ◽  
Tumor Vaccines ◽  
Therapeutic Vaccines ◽  
Important Field

Abstract Personalized therapeutic vaccines against immune desert tumors are an increasingly important field in current cancer immunotherapy. However, limitations in neoantigen recognition, impotent immune cells, and a lack of intratumoral infiltrated lymphocytes pose challenges for the cancer vaccines. Resected tumors contain various of patient-specific tumor autoantigens (TA), and its derived photonanovaccines have unique competency to overcome abovementioned barriers. We constructed a novel personalized photonanovaccine (B@TA-R848) with surgically sourced TA modified on two-dimensional boron nanosheets (BNSs) via polydopamine coating and loaded with immune adjuvant R848. B@TA-R848 has good properties of drug delivery and release, photoacoustic imaging, photothermal effect, and biocompatibility. In a mouse triple-negative breast cancer model, B@TA-R848-based photonanovaccine induced effective systemic antitumor immune responses, altered the local tumor microenvironment, and increased the intratumoral infiltration of immune cells. The combined photo immunotherapy could significantly inhibit tumor growth, recurrence, and metastasis. This work develops a novel photonanovaccine for low immunogenicity and high metastatic potential tumors, which is of great significance for exploring the clinical development of personalized tumor vaccines against immune desert tumors.

A Hypoxia-related LncRNA Signature Predicts Survival of Primary Lower-grade glioma

2021 ◽  
Author(s):  
Yanjia Hu ◽  
Jing Zhang ◽  
Jing Chen
Keyword(s):  
High Risk ◽  
Risk Score ◽  
Cox Regression ◽  
Risk Group ◽  
Enrichment Analysis ◽  
High Risk Group ◽  
Gene Set Enrichment Analysis ◽  
Lower Grade ◽  
Prognostic Signature ◽  
Gene Set Enrichment

Abstract Background Hypoxia-related long non-coding RNAs (lncRNAs) have been proven to play a role in multiple cancers and can serve as prognostic markers. Lower-grade gliomas (LGGs) are characterized by large heterogeneity. Methods This study aimed to construct a hypoxia-related lncRNA signature for predicting the prognosis of LGG patients. Transcriptome and clinical data of LGG patients were obtained from The Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA). LGG cohort in TCGA was chosen as training set and LGG cohorts in CGGA served as validation sets. A prognostic signature consisting of fourteen hypoxia-related lncRNAs was constructed using univariate and LASSO Cox regression. A risk score formula involving the fourteen lncRNAs was developed to calculate the risk score and patients were classified into high- and low-risk groups based on cutoff. Kaplan-Meier survival analysis was used to compare the survival between two groups. Cox regression analysis was used to determine whether risk score was an independent prognostic factor. A nomogram was then constructed based on independent prognostic factors and assessed by C-index and calibration plot. Gene set enrichment analysis and immune cell infiltration analysis were performed to uncover further mechanisms of this lncRNA signature. Results LGG patients with high risk had poorer prognosis than those with low risk in both training and validation sets. Recipient operating characteristic curves showed good performance of the prognostic signature. Univariate and multivariate Cox regression confirmed that the established lncRNA signature was an independent prognostic factor. C-index and calibration plots showed good predictive performance of nomogram. Gene set enrichment analysis showed that genes in the high-risk group were enriched in apoptosis, cell adhesion, pathways in cancer, hypoxia etc. Immune cells were higher in high-risk group. Conclusion The present study showed the value of the 14-lncRNA signature in predicting survival of LGGs and these 14 lncRNAs could be further investigated to reveal more mechanisms involved in gliomas.

scholarly journals The Safety of an Adjuvanted Autologous Cancer Vaccine Platform in Canine Cancer Patients

2018 ◽  
Vol 5 (4) ◽  
pp. 87 ◽  
Author(s):  
Chris Weir ◽  
Annika Oksa ◽  
Jennifer Millar ◽  
Miles Alexander ◽  
Nicola Kynoch ◽  
...  
Keyword(s):  
Adverse Reactions ◽  
Tumor Antigens ◽  
Autologous Tumor ◽  
Tumor Vaccines ◽  
Vaccine Platform ◽  
Safety Study ◽  
Diverse Range ◽  
Canine Cancer ◽  
Ongoing Development ◽  
Vaccine Approach

Canine cancer rates are similar to humans, though the therapeutic options might be limited. Inducing a patient’s own immune system to have an anti-tumor response is an attractive approach to cancer therapy. In this safety study, autologous tumor vaccines produced specifically for each canine patient were combined with Advax™, a novel non-inflammatory immunomodulator and vaccine adjuvant and were tested for safety in a diverse range of patient presentations alone or in combination with other treatments. Canine patients had their tumor biopsied, debulked or resected and the tumor antigens were processed into an autologous vaccine formulated with Advax™ adjuvant with or without rhizavidin as an additional immune stimulant. Patients treated early in the trial received two intramuscular (IM) doses, 2 weeks apart. As the study progressed and no issues of safety were observed, the protocol was changed to weekly vaccinations for 4 weeks followed by monthly booster shots. Over the 150 I.M injections delivered to date, the vaccine was found to be very safe and no significant adverse reactions were observed. These results justify ongoing development and future controlled studies of this autologous vaccine approach.

scholarly journals Structures suggest an approach for converting weak self-peptide tumor antigens into superagonists for CD8 T cells in cancer

2021 ◽  
Vol 118 (23) ◽  
pp. e2100588118
Author(s):  
Pengcheng Wei ◽  
Kimberly R. Jordan ◽  
Jonathan D. Buhrman ◽  
Jun Lei ◽  
Hexiang Deng ◽  
...  
Keyword(s):  
T Cells ◽  
Amino Acid ◽  
T Cell ◽  
Amino Acid Substitution ◽  
Cd8 T Cells ◽  
Tumor Antigens ◽  
Vaccine Development ◽  
Single Amino Acid ◽  
Cell Repertoire ◽  
Subtle Change

Tumors frequently express unmutated self-tumor–associated antigens (self-TAAs). However, trial results using self-TAAs as vaccine targets against cancer are mixed, often attributed to deletion of T cells with high-affinity receptors (TCRs) for self-TAAs during T cell development. Mutating these weak self-TAAs to produce higher affinity, effective vaccines is challenging, since the mutations may not benefit all members of the broad self-TAA–specific T cell repertoire. We previously identified a common weak murine self-TAA that we converted to a highly effective antitumor vaccine by a single amino acid substitution. In this case the modified and natural self-TAAs still raised very similar sets of CD8 T cells. Our structural studies herein show that the modification of the self-TAA resulted in a subtle change in the major histocompatibility complex I–TAA structure. This amino acid substitution allowed a dramatic conformational change in the peptide during subsequent TCR engagement, creating a large increase in TCR affinity and accounting for the efficacy of the modified self-TAA as a vaccine. These results show that carefully selected, well-characterized modifications to a poorly immunogenic self-TAA can rescue the immune response of the large repertoire of weakly responding natural self-TAA–specific CD8 T cells, driving them to proliferate and differentiate into functional effectors. Subsequently, the unmodified self-TAA on the tumor cells, while unable to drive this response, is nevertheless a sufficient target for the CD8 cytotoxic effectors. Our results suggest a pathway for more efficiently identifying variants of common self-TAAs, which could be useful in vaccine development, complementing other current nonantigen-specific immunotherapies.

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