This study aimed to develop a vaccine that targets mutation-derived neoantigen in Chinese non-small-cell lung cancer (NSCLC).
A cohort of 1862 Chinese NSCLC patients who underwent targeted sequencing ...with a 1021-gene panel was investigated. HLA typing was done using OptiType v1.0 and neoantigens were predicted by netMHCpan v4.0. HLA LOH was inferred using the lohhla algorithm and TMB were quantified by counting the total number of non-synonymous ones based on our panel data. CIBERSORT was utilized to estimate the TME in different
mutant subtype by using TCGA data.
HLA-A*11:01(42.59%) was the top one allele and HLA-A*33:03(12.94%) ranked 12th.
L858R (22.61%) was the most prevalent gene variant. The binding affinity (IC50 MT = 22.9 nM) and shared frequency (2.93%) of
L858R in combination with HLA-A*33:03 were optimal. In a subsequent further analysis on immunological features of
mutant subtypes, 63.1% HLA loss of heterozygosity LOH (HLA LOH) and 0.37% (7 of 1862) B2M aberrations were found in our population, both had no significant association with
mutant subtypes suggesting that the process of antigen presentation involved HLA LOH and B2M mechanisms in
L858R is working. Tumor mutation burden (TMB) was investigated by utilizing our panel and showed that
L858R had the lowest TMB compared with other
mutant subtypes. In addition, analysis of 22 immune cell types from The Cancer Genome Atlas (TCGA) data showed
L858R was correlated with low level of CD8 T cells, activated CD4 memory T cells and elevated level of macrophage M2 suggesting an inhibited tumor microenvironment (TME).
Our study identified that
L858R neoantigen had the potential to generate cancer vaccines in NSCLC patients with HLA A*33:03. The neoantigen-based vaccines may become an effective salvage regimen for
L858R subgroup after targeted therapy or immune checkpoint inhibitors (ICIs) failure.
Immunotherapy has become a research hotspot and is used for head and neck cancer treatment. This research aims to explore the prognostic value of PYHIN1 in oral cancer and the relationship between ...PYHIN1 and cancer immunity.
The expression of PYHIN1 in clinical specimens was evaluated by bioinformatics analyses and immunohistochemistry.
Gene ontology term enrichment analyses and gene set enrichment analyses showed the involvement of PYHIN1 in the modulation of adaptive immunity-associated signaling according to The Cancer Genome Atlas database and Gene Expression Omnibus dataset. Interestingly, the correlation analyses in The Cancer Genome Atlas database revealed a positive correlation between PYHIN1 expression and activated CD8+ T cells infiltration and a negative correlation between PYHIN1 expression and tumor purity. Moreover, activated CD8+ T cells infiltration predicted good patient survival and was negatively correlated with tumor purity. Importantly, PYHIN1 expression was negatively correlated with the pathological stage and was positively associated with a good prognosis in patients with oral cancer. The data obtained from the Gene Expression Omnibus dataset and immunohistochemistry confirmed the positive association between PYHIN1 and CD8+ T cells infiltration in oral cancer tissues.
We conclude that PYHIN1 is an indicator of cancer immunity, and is an independent prognostic factor that may be an alternative target for oral cancer treatment.
Immunogenic cell death (ICD) is a type of regulated cell death that can activate adaptive immune response, and its ability to reshape the tumor microenvironment via multiple mechanisms may contribute ...to immunotherapy. The treatment options for patients with skin cutaneous melanoma (SKCM) vary based on BRAF V600E statuses. However, all standard treatments include immunotherapy. Therefore, it is critical to identify ICD-associated signatures that can help classify patients according to benefits from ICD immunotherapy. In this study, data on melanoma samples with BRAF V600E mutation (BRAF V600E-mutant melanoma) and melanoma samples with wild-type BRAF V600E alleles (BRAF V600E WT melanoma) were collected from The Cancer Genome Atlas (TCGA) database. The ICD-related (ICD-high and ICD-low) subgroups of patients with BRAF V600E WT melanoma were established via consensus clustering. The analyses of survival, differentially expressed genes (DEGs), functional annotation, and immune landscape were performed in these two subgroups. Results showed that ICD-high subgroup was correlated with a positive overall survival (OS) and active tumor immune landscape. A model comprising seven prognosis ICD-related gene biomarkers was developed. Survival analysis and receiver operating characteristic (ROC) curve evaluation in both cohorts with BRAF V600E WT and BRAF V600E-mutant melanoma showed an accurate prognostic estimation of ICD-related risk signature. There was a correlation between immune cell infiltration and immunotherapy response and risk score. Thus, the ICD risk signature was closely associated with the tumor’s immune microenvironment. Our results may provide insights to further individualize and improve precision therapeutic decision-making in BRAF V600E-mutant and WT melanoma.
Long noncoding RNAs (lncRNAs) regulate cancer cell senescence in many cancers. However, their specific involvement in head and neck squamous cell carcinoma (HNSCC) remains unclear. We are looking for ...an ingenious prognostic signature that utilizes senescence-related lncRNAs (SRlncRNAs) to predict prognosis and provide insights into the immune landscape in HNSCC.
HNSCC clinical and Cellular senescence genes information were collected from The Cancer Genome Atlas and Human Aging Genomic Resources. Then we performed Cox and Lasso regression to locate SRlncRNAs related to the prognosis of HNSCC and built a predictive signature. Further, prognosis assessment, potential mechanisms, and immune status were assessed by Kaplan-Meier analysis, Gene Set Enrichment Analysis (GSEA), and CIBERSORT, respectively.
A prognosis prediction model based on sixteen SRlncRNAs was identified and internally validated. Then, patients with high-risk scores suffered an unfavorable overall survival (All p < 0.05). The risk score, age, and stage were independent prognostic parameters (all p < 0.001). Our model has good predictive ability (The AUC (area under the curves) 1-year = 0.707, AUC3-year = 0.748 and AUC5-year = 0.779). Subsequently, GESA revealed SRlncRNAs regulated immune responses. Patients in the high-risk group had higher tumor mutation burden and Tumor Immune Dysfunction and Exclusion but lower levels of 37 immune checkpoint genes, immune scores, and immune cells like CD8 + T cells, follicular helper T cells, and regulatory T cells.
A prognostic model based on SRlncRNAs is the potential target for improving immunotherapy outcomes for HNSCC.
Nasopharyngeal carcinoma (NPC) is a malignant epithelial tumor originating in the nasopharynx and has a high incidence in Southeast Asia and North Africa. To develop these comprehensive guidelines ...for the diagnosis and management of NPC, the Chinese Society of Clinical Oncology (CSCO) arranged a multi‐disciplinary team comprising of experts from all sub‐specialties of NPC to write, discuss, and revise the guidelines. Based on the findings of evidence‐based medicine in China and abroad, domestic experts have iteratively developed these guidelines to provide proper management of NPC. Overall, the guidelines describe the screening, clinical and pathological diagnosis, staging and risk assessment, therapies, and follow‐up of NPC, which aim to improve the management of NPC.
Background
Immunogenic cell death (ICD) has been categorized as a variant of regulated cell death that is capable of inducing an adaptive immune response. A growing body of evidence has indicated ...that ICD can modify the tumor immune microenvironment by releasing danger signals or damage-associated molecular patterns (DAMPs), potentially enhancing the efficacy of immunotherapy. Consequently, the identification of biomarkers associated with ICD that can classify patients based on their potential response to ICD immunotherapy would be highly advantageous. Therefore the goal of the study is to better understand and identify what patients with bladder urothelial carcinoma (BLCA) will respond to immunotherapy by analyzing ICD signatures and investigate ICD-related prognostic factors in the context of BLCA.
Methods
The data obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases regarding BLCA and normal samples was categorized based on ICD-related genes (IRGs). Specifically, we conducted an immunohistochemical (IHC) experiment to validate the expression levels of Calreticulin (CALR) in both tumor and adjacent tissues, and evaluated its prognostic significance using the Kaplan-Meier (KM) curve. Subsequently, the samples from TCGA were divided into two subtypes using consensus clustering. To obtain a more comprehensive comprehension of the biological functions, we utilized Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA). The calculation of immune landscape between two subtypes was performed through ESTIMATE and CIBERSORT. Risk models were constructed using Cox and Lasso regression and their prognosis predictive ability was evaluated using nomogram, receiver operating characteristic (ROC), and calibration curves. Finally, Tumor Immune Dysfunction and Exclusion (TIDE) algorithms was utilized to predict the response to immunotherapy.
Results
A total of 34 IRGs were identified, with most of them exhibiting upregulation in BLCA samples. The expression of CALR was notably higher in BLCA compared to the adjacent tissue, and this increase was associated with an unfavorable prognosis. The differentially expressed genes (DEGs) associated with ICD were linked to various immune-related pathways. The ICD-high subtypes exhibited an immune-activated tumor microenvironment (TME) compared to the ICD-low subtypes. Utilizing three IRGs including
CALR
,
IFNB1
, and
IFNG
, a risk model was developed to categorize BLCA patients into high- and low-risk groups. The overall survival (OS) was considerably greater in the low-risk group compared to the high-risk group, as evidenced by both the TCGA and GEO cohorts. The risk score was identified as an independent prognostic parameter (all
p
< 0.001). Our model demonstrated good predictive ability (The area under the ROC curve (AUC), AUC
1
-year= 0.632, AUC
3
-year= 0.637, and AUC
5
-year =0.653). Ultimately, the lower risk score was associated with a more responsive immunotherapy group.
Conclusion
The potential of the ICD-based risk signature to function as a marker for evaluating the prognosis and immune landscape in BLCA suggests its usefulness in identifying the suitable population for effective immunotherapy against BLCA.
Background. Globally, head and neck squamous cell carcinoma (HNSCC) is a common malignant tumor with high morbidity and mortality. Hence, it is important to find effective biomarkers for the ...diagnosis and prediction of the prognosis of patients with HNSCC. FAM3D had been proven to be vital in other cancers. However, its predictive and therapeutic value in HNSCC is unclear. Therefore, it is valuable to explore the association between the expression level of FAM3D and its impacts on the prognosis and tumor microenvironment in HNSCC. Methods. The Cancer Genome Atlas (TCGA) dataset, Genotype-Tissue Expression (GTEx) dataset, the Clinical Proteomic Tumor Analysis Consortium (CPTAC) dataset, and The Human Protein Atlas (THPA) website were used to assess HNSCC expressions in tumor and nontumor tissues. Then, we further conducted immunohistochemistry experiment as internal cohort to validate the same results. The Cox regression analysis, Kaplan–Meier analysis, and nomograms were performed to find the predictive prognostic value of FAM3D in HNSCC patients and its relationship with the clinicopathological features in HNSCC. The Gene Expression Omnibus (GEO) dataset was utilized to externally verify the prognosis value of FAM3D in HNSCC. Gene Set Enrichment Analysis (GESA) was applied to search the molecular and biological functions of FAM3D. The association between FAM3D and immune cell infiltration was investigated with the Tumor Immune Estimating Resource, version 2 (TIMER2). The relationships between FAM3D expression and tumor microenvironment (TME) scores, immune checkpoints, and antitumor compound half-maximal inhibitory concentration predictions were also explored. Results. In different datasets, FAM3D mRNA and protein levels were all significantly lower in HNSCC tissues than in normal tissues, and they were strongly inversely associated with tumor grade, stage, lymph node metastasis, and T stage. Patients with high-FAM3D-expression displayed better prognosis than those with low-FAM3D-expression. FAM3D was also determined to be a suitable biomarker for predicting the prognosis of patients with HNSCC. This was externally validated in the GEO dataset. As for gene and protein level, the functional and pathway research results of FAM3D indicated that it was enriched in alteration of immune-related pathways in HNSCC. The low-expression group had higher stromal and ESTIMATE scores by convention than the high-expression group. FAM3D expression were found to be positively correlated with immune infiltrating cells, such as cancer-associated fibroblasts, myeloid-derived suppressor cells, macrophage cells, T cell CD8+ cells, regulatory T cells, and T cell follicular helper cells. FAM3D’s relationships with immune checkpoints and sensitivity to antitumor drugs were also investigated. Conclusion. Our study explored the impact of FAM3D as a favorable prognostic marker for HNSCC on the tumor immune microenvironment from multiple perspectives. The results may provide new insights into HNSCC-targeted immunotherapy.
Importance Immune checkpoint inhibitors (ICIs) can elicit durable antitumor responses in patients with non–small cell lung cancer (NSCLC), but only 20% to 25% of patients respond to treatment. As ...important genes in the DNA damage response pathway, comutation in the tumor protein p53 (TP53) and ataxia-telangiectasia mutated (ATM) genes may be associated with genomic instability and hypermutation. However, the prevalence ofTP53andATMcomutation and its association with response to ICIs are not fully understood. Objective To examine the prevalence of theTP53andATMcomutation, the potential mechanism, and its association with response to ICIs among patients with NSCLC. Design, Setting, and Participants This multiple-cohort study included patients with NSCLC from the Geneplus Institute, the Cancer Genome Atlas (TCGA), and the Memorial Sloan Kettering Cancer Center (MSKCC) databases and from the POPLAR and OAK randomized controlled trials. Samples in the Geneplus cohort were collected and analyzed from April 30, 2015, through February 28, 2019. Data from TCGA, the MSKCC, and the POPLAR and OAK cohorts were obtained on January 1, 2019, and analyzed from January 1 to April 10, 2019. Next-generation sequencing assays were performed on tumor samples by the Geneplus Institute. Genomic, transcriptomic, and clinical data were obtained from TCGA and MSKCC databases. Exposures Comprehensive genetic profiling was performed to determine the prevalence ofTP53andATMcomutation and its association with prognosis and response to ICIs. Main Outcomes and Measures The main outcomes wereTP53andATMcomutation frequency, overall survival (OS), progression-free survival, gene set enrichment analysis, and immune profile in NSCLC. Results Patients with NSCLC analyzed in this study included 2020 patients in the Geneplus cohort (mean SD age, 59.5 10.5 years; 1168 57.8% men), 1031 patients in TCGA cohort (mean SD age, 66.2 9.5 years; 579 56.2% men), 1527 patients in the MSKCC cohort (662 43.4% men), 350 patients in the MSKCC cohort who were treated with ICIs (mean SD age, 61.4 13.8 years; 170 48.6% men), and 853 patients in the POPLAR and OAK cohort (mean SD age, 63.0 9.1 years; 527 61.8% men). Sites ofTP53andATMcomutation were found scattered throughout the genes, and no significant difference was observed in the frequency ofTP53andATMcomutation within the histologic subtypes and driver genes. In 5 independent cohorts of patients with NSCLC,TP53andATMcomutation was associated with a significantly higher tumor mutation burden compared with the sole mutation and with no mutation (TCGA, MSKCC, Geneplus, and POPLAR and OAK cohort). Among patients treated with ICIs in the MSKCC cohort,TP53andATMcomutation was associated with better OS than a single mutation and no mutation among patients with any cancer (median OS:TP53andATMcomutation, not reached;TP53mutation alone, 14.0 months;ATMmutation alone, 40.0 months; no mutation, 22.0 months;P = .001; NSCLC median OS:TP53andATMcomutation, not reached;TP53mutation alone, 11.0 months;ATMmutation alone, 16.0 months; no mutation, 14.0 months;P = .24). Similar results were found in the POPLAR and OAK cohort in which the disease control benefit rate, progression-free survival, and OS were all greater in patients with theTP53andATMcomutation compared with the other 3 groups (median progression-free survival:TP53andATMcomutation, 10.4 months;TP53mutation, 1.6 months;ATMmutation, 3.5 months; no mutation, 2.8 months;P = .01; median OS:TP53andATMcomutation, 22.1 months;TP53mutation, 8.3 months;ATMmutation, 15.8 months; no mutation, 15.3 months;P = .002). Conclusions and Relevance This study’s findings suggest that theTP53andATMcomutation occurs in a subgroup of patients with NSCLC and is associated with an increased tumor mutation burden and response to ICIs. This suggests thatTP53andATMcomutation may have implications as a biomarker for guiding ICI treatment.
To evaluate the efficacy and safty of the humanized anti-epidermal factor receptor monoclonal antibody h-R3 in combination with radiotherapy for locoregionally advanced nasopharyngeal carcinoma.
...Totally, 137 patients from 7 medical center around China were randomly divided into combined therapy group or control group. There was no difference in Karnofsky performance score between two groups. All patients in both groups received radical conventionally fractionated radiotherapy to the total dose of D(T) 70-76 Gy. For the combined therapy group, h-R3 was added at a dose of 100 mg i.v. weekly for 8 weeks started at the beginning of radiotherapy.
Of the 137 eligilbe patients, 70 were in the combined therapy group treated by h-R3 plus radiotherapy and 67 in the control group by radiotherapy alone. The intent-to-treat (ITT) population consisted of 130 patients, while the per-protocol (PP) population was composed of 126 patients. The efficacy was assessed respectively at three point of time: the end of treatment, the
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