High Immune Cell Infiltration Research Articles

Whole-transcriptome defines novel glucose metabolic subtypes in colorectal cancer.

Colorectal cancer (CRC) is the most prevalent malignancy of the digestive system. Glucose metabolism plays a crucial role in CRC development. However, the heterogeneity of glucose metabolic patterns in CRC is not well characterized. Here, we classified CRC into specific glucose metabolic subtypes and identified the key regulators. 2228 carbohydrate metabolism-related genes were screened out from the GeneCards database, 202 of them were identified as prognosis genes in the TCGA database. Based on the expression patterns of the 202 genes, three metabolic subtypes were obtained by the non-negative matrix factorization clustering method. The C1 subtype had the worst survival outcome and was characterized with higher immune cell infiltration and more activation in extracellular matrix pathways than the other two subtypes. The C2 subtype was the most prevalent in CRC and was characterized by low immune cell infiltration. The C3 subtype had the smallest number of individuals and had a better prognosis, with higher levels of NRF2 and TP53 pathway expression. Secreted frizzled-related protein 2 (SFRP2) and thrombospondin-2 (THBS2) were confirmed as biomarkers for the C1 subtype. Their expression levels were elevated in high glucose condition, while their knockdown inhibited migration and invasion of HCT 116 cells. The analysis of therapeutic potential found that the C1 subtype was more sensitive to immune and PI3K-Akt pathway inhibitors than the other subtypes. To sum up, this study revealed a novel glucose-related CRC subtype, characterized by SFRP2 and THBS2, with poor prognosis but possible therapeutic benefits from immune and targeted therapies.

The tertiary lymphoid structure-related signature identified PTGDS in regulating PD-L1 and promoting the proliferation and migration of glioblastoma

BackgroundTertiary lymphoid structure (TLS) is a unique organ that carries out tumor cell elimination at tumor sites. It is continuously stimulated by inflammatory tumor signals and has been found to augment immunotherapy response. However, the detailed mechanisms behind it still need to be defined. MethodsTo explore and grasp the whole picture of TLS from a pan-cancer view, we collected nine TLS-related genes from previous studies. We performed a comprehensive analysis of 9637 samples across 33 tumor types accessed from The Cancer Genome Atlas (TCGA) database. EdU, Transwell, and flow cytometry were performed on the feature gene PTGDS in U251 cells. The regulatory role of PTGDS on PD-L1 expression and macrophage polarization was verified. ResultsAlteration analysis showed that mutations of TLS-related genes were widespread and relatively high. Clustering analysis based on the expression of these nine genes obtained two distinct clusters, with high EIF1AY and PTGDS in cluster 2 and better overall survival in cluster 1. To distinguish the two clusters, we utilized six machine learning algorithms and filtrated EIF1AY, PTGDS, SKAP1, and RBP5 as the characteristic genes, among which the former two genes were proved to be hazardous. PTGDS was found to regulate PD-L1 expression and also promoted the proliferation and migration of U251 cells. The knockdown of PTGDS could reduce the migration of macrophages and inhibit the polarization of macrophages into M2-phenotype. In addition, we established a TLS score to demonstrate patients’ TLS activity. The low TLS-score group overlapped with cluster 1 and displayed a better prognosis. Besides, the low TLS-score group was related to better immunotherapy responses. The HE staining of histopathological sections confirmed that the low TLS-score group exhibited higher infiltration of immune cells. ConclusionThis study reveals broad molecular, tumorigenic, and immunogenic signatures for further functional and therapeutic studies of tertiary lymphoid structure. The TLS score we established effectively predicted immunotherapy response and patients’ survival. Its future application and combination await more research.

Identification of molecular subtypes and prognostic model to reveal immune infiltration and predict prognosis based on immunogenic cell death-related genes in lung adenocarcinoma

ABSTRACT Immunogenic cell death (ICD) has been increasingly indicated to be related to caners. However, ICD’s role in Lung adenocarcinoma (LUAD) is still not well investigated. Clinical data along with associated mRNA expression profiles from LUAD cases were collected in TCGA and GEO databases. 13 ICD-related genes were identified. Relations of ICD-related genes expression with prognosis of patients, tumor immune microenvironment (TIME) was analyzed. Then, candidate genes were identified and the prognostic signature were constructed. Afterwards, one nomogram incorporating those chosen clinical data together with risk scores were built. Finally, the effect of HSP90AA1, one gene of the prognostic signature, on LUAD cell were analyzed. Two clusters were identified, which were designated as the ICD-high or -low subtype according to ICD-related genes levels. ICD-high subgroup showed good prognosis, high immune cell infiltration degrees, and enhanced immune response signaling activity compared with ICD-low subtype. Moreover, we established and verified the risk signature based on ICD-related genes. High risk group predicted poor prognosis of LUAD independently and presented negative association with immune score and immune status. Furthermore, nomogram contributed to the accurate prediction of LUAD prognostic outcome. Finally, HSP90AA1 levels were remarkably elevated within tumor cells in comparison with healthy pulmonary epithelial cells. HSP90α, HSP90AA1 protein product, promoted growth, migration, and invasion of LUAD cells. Molecular subtypes and prognostic model were identified by incorporating ICD-related genes, and it was related to TIME and might be adopted for the accurate prediction of LUAD prognosis.

Comprehensive molecular analysis identifies RET alterations association with response of ICIs in multi-immunotherapy cohorts

BackgroundThe RET gene, which is frequently mutated across many types of cancer, has been proven to be critically involved in tumorigenesis and tumour development; however, its prediction of the therapeutic efficacy of immune checkpoint inhibitor (ICI) therapy remains to be elucidated. The present research aims to investigate the association between RET mutations and the efficiency of ICI therapy. MethodWe analysed the role of RET mutations in predicting the prognosis of patients receiving ICIs therapy in the discovery cohort and validated it in the validation cohort. Then, multi-omics data from TCGA pan-cancer cohort was employed to propose the association between RET mutations and tumour inflamed anti-tumour immune response and tumour antigenicity. ResultsOur study revealed that among 606 cases and across five types of cancer, RET mutation was associated with better clinical outcomes for ICIs therapy, including elevated response rate, longer progression-free survival PFS, and longer overall survival OS. Multivariate analysis showed that RET mutation could independently predict the prognosis of patients treated with ICIs, after adjusting cancer types. The predictive value of RET status for the OS of patients treated with ICIs immunotherapy was further validated in the validation cohort (n = 1,409). Subgroup analysis suggested that only the monotherapy group showed significant differences in OS(P < 0.05) and PFS(P < 0.05) between RET-wildtype tumours and RET-mutant tumours. Multi-omics data analysis revealed potential anti-tumour immunity mechanisms of RET mutations, suggesting that RET-mutant tumours have enhanced immunogenicity, higher expression of immune checkpoints and chemokines, and higher immune cell infiltration than those observed in RET-wildtype tumours; thus, potentially indicating a more favourable response to immunotherapy. ConclusionsRET mutation may be a predictive biomarker of enhanced response to ICIs therapy. Extensive investigation of the underlying molecular mechanisms and prospective studies are needed in the future.

Bioinformatics analysis of immune characteristics in tumors with alternative carcinogenesis pathways induced by human papillomaviruses

BackgroundHuman papillomaviruses (HPVs) induce a subset of head and neck squamous cell carcinomas (HNSCC) and anogenital cancers, particularly cervical cancer (CC). The major viral proteins that contribute to tumorigenesis are the E6 and E7 oncoproteins, whose expression is usually enhanced after the integration of viral DNA into the host genome. Recently, an alternative tumorigenesis pathway has been suggested in approximately half of HNSCC and CC cases associated with HPV infection. This pathway is characterized by extrachromosomal HPV persistence and increased expression of the viral E2, E4, and E5 genes. The E6, E7, E5, and E2 proteins have been shown to modify the expression of numerous cellular immune-related genes. The antitumor immune response is a critical factor in the prognosis of HPV-driven cancers, and its characterization may contribute to the prediction and personalization of the increasingly used cancer immunotherapy.MethodsWe analyzed the immune characteristics of HPV-dependent tumors and their association with carcinogenesis types. Transcriptomic HNSCC and CC datasets from The Cancer Genome Atlas were used for this analysis.ResultsClustering with immune-related genes resulted in two clusters of HPV16-positive squamous cell carcinomas in both tumor types: cluster 1 had higher activation of immune responses, including stimulation of the antigen processing and presentation pathway, which was associated with higher immune cell infiltration and better overall survival, and cluster 2 was characterized by keratinization. In CC, the distribution of tumor samples into clusters 1 and 2 did not depend on the level of E2/E5 expression, but in HNSCC, most E2/E5-high tumors were localized in cluster 1 and E2/E5-low tumors in cluster 2. Further analysis did not reveal any association between the E2/E5 levels and the expression of immune-related genes.ConclusionsOur results suggest that while the detection of immune responses associated with preserved expression of genes encoding components of antigen processing and presentation machinery in HPV-driven tumors may be markers of better prognosis and an important factor in therapy selection, the type of carcinogenesis does not seem to play a decisive role in the induction of antitumor immunity.

High tumour mutational burden is associated with strong PD-L1 expression, HPV negativity, and worse survival in penile squamous cell carcinoma: an analysis of 165 cases

Penile squamous cell carcinoma (pSCC) is a rare tumour with a variable prognosis. More prognostic markers linked to mutational signatures and the tumour immune microenvironment are needed. A cohort made up of 165 invasive pSCC was retrospectively analysed using formalin-fixed, paraffin-embedded tumour tissue, focusing on tumour mutational burden (TMB), programmed death ligand 1 (PD-L1) expression, microsatellite instability (MSI), the number of tumour infiltrating lymphocytes (TILs) expressing cytotoxic T-lymphocyte-associated protein 4 (CTLA4), HPV status determined by p16 immunohistochemistry, and several traditional histopathological variables. High TMB (>10 mut/Mb) was associated with high PD-L1 expression (TPS 50-100%), and HPV-negative status. High PD-L1 expression was linked to HPV negativity, a high number of intratumoural CTLA4+ cells, and brisk lymphocytic infiltrate. High TMB was a significant predictor of shorter overall survival (OS) in both univariate and multivariate analysis when using a median cut-off value of 4.3 mut/Mb, but not when using an arbitrary cut-off of 10 mut/Mb. Low CTLA4+ cell infiltration at the tumour invasion front was a marker of shorter OS and cancer-specific survival in both univariate and multivariate analysis. PD-L1 expression had no significant impact on prognosis. Only two cases were MSI high. The results support the hypothesis of two aetiological pathways in pSCC cancerogenesis: (1) SCC linked to HPV infection characterised by low TMB, less common PD-L1 expression, and a lower number of TILs; and (2) SCC linked to chronic inflammation leading to a high number of acquired mutations (high TMB), HPV negativity, increased neoantigen production (i.e., PD-L1), and high immune cell infiltration.

Opposing roles by KRAS and BRAF mutation on immune cell infiltration in colorectal cancer – possible implications for immunotherapy

BackgroundThe immune response has important clinical value in colorectal cancer (CRC) in both prognosis and response to immunotherapy. This study aims to explore tumour immune cell infiltration in relation to clinically well-established molecular markers of CRC.MethodsMultiplex immunohistochemistry and multispectral imaging was used to evaluate tumour infiltration of cytotoxic T cells (CD8+), Th1 cells (T-bet+), T regulatory cells (FoxP3+), B cells (CD20+), and macrophages (CD68+) in a cohort of 257 CRC patients.ResultsWe found the expected association between higher immune-cell infiltration and microsatellite instability. Also, whereas BRAF-mutated tumours displayed increased immune-cell infiltration compared to BRAF wild-type tumours, the opposite was seen for KRAS-mutated tumours, differences that were most prominent for cytotoxic T cells and Th1 cells. The opposing relationships of BRAF and KRAS mutations with tumour infiltration of cytotoxic T cells was validated in an independent cohort of 608 CRC patients. A positive prognostic importance of cytotoxic T cells was found in wild-type as well as KRAS and BRAF-mutated CRCs in both cohorts.ConclusionA combined evaluation of MSI status, KRAS and BRAF mutational status, and immune infiltration (cytotoxic T cells) may provide important insights to prognosis and response to immunotherapy in CRC.

Value of TMEM115 as a Potential Prognostic Biomarker in Liver Hepatocellular Carcinoma

Transmembrane protein 115 (TMEM115) is a membrane protein; considering the potential of membrane proteins as biomarkers for various pathological conditions, we aimed to examine the value of TMEM115 as a potential biomarker for improving the prognosis and treatment of liver hepatocellular carcinoma (LIHC) in this study. Online databases including the Tumor Immune Estimation Resource, UALCAN, Gene Expression Profiling Interactive Analysis version 2, OSlihc, and human Protein Atlas were used. The analysis suggested that TMEM115 expression in LIHC was higher compared to normal tissues; further, TMEM115 expression was confirmed to be related with poor prognosis in LIHC. Higher protein expression levels of TMEM115 were observed in LIHC tissues than in normal tissues. Tumor infiltration by immune cells was confirmed to be correlated with the expression of TMEM115. High TMEM115 expression and immune cell infiltration were further related to poor prognosis in LIHC. We also confirmed a correlation between TMEM115 and TP53 mutations. In conclusion, we confirmed that TMEM115 expression is correlated with tumor-infiltrating immune cells and poor prognosis in LIHC and that TMEM115 shows potential as a prognostic biomarker in LIHC.

The Communication from Immune Cells to the Fibroblasts in Keloids: Implications for Immunotherapy.

Keloids are a type of fibrotic disease characterized by excessive collagen production and extracellular matrix (ECM) deposition. The symptoms of pain and itching and frequent recurrence after treatment significantly impact the quality of life and mental health of patients. A deeper understanding of the pathogenesis of keloids is crucial for the development of an effective therapeutic approach. Fibroblasts play a central role in the pathogenesis of keloids by producing large amounts of collagen fibers. Recent evidence indicates that keloids exhibit high immune cell infiltration, and these cells secrete cytokines or growth factors to support keloid fibroblast proliferation. This article provides an update on the knowledge regarding the keloid microenvironment based on recent single-cell sequencing literature. Many inflammatory cells gathered in keloid lesions, such as macrophages, mast cells, and T lymphocytes, indicate that keloids may be an inflammatory skin disease. In this review, we focus on the communication from immune cells to the fibroblasts and the potential of immunotherapy for keloids. We hope that this review will trigger interest in investigating keloids as an inflammatory disease, which may open up new avenues for drug development by targeting immune mediators.

Single-cell transcriptomic analysis of gingivo-buccal oral cancer reveals two dominant cellular programs.

Oral squamous cell carcinoma of the gingivo-buccal region (OSCC-GB) is the most common cancer among men in India, and is associated with poor prognosis and frequent recurrence. Cellular heterogeneity in OSCC-GB was investigated by single-cell RNA sequencing of tumors derived from the oral cavity of 12 OSCC-GB patients, 3 of whom had concomitant presence of a precancerous lesion (oral submucous fibrosis [OSMF]). Unique malignant cell types, features, and phenotypic shifts in the stromal cell population were identified in oral tumors with associated submucous fibrosis. Expression levels of FOS, ATP1A, and DUSP1 provided robust discrimination between tumors with or without the concomitant presence of OSMF. Malignant cell populations shared between tumors with and without OSMF were enriched with the expression of partial epithelial-mesenchymal transition (pEMT) or fetal cell type signatures indicative of two dominant cellular programs in OSCC-GB-pEMT and fetal cellular reprogramming. Malignant cells exhibiting fetal cellular and pEMT programs were enriched with the expression of immune-related pathway genes known to be involved in antitumor immune response. In the tumor microenvironment, higher infiltration of immune cells than the stromal cells was observed. The T cell population was large in tumors and diverse subtypes of T cells with varying levels of infiltration were found. We also detected double-negative PLCG2+ T cells and cells with intermediate M1-M2 macrophage polarization. Our findings shed light on unique aspects of cellular heterogeneity and cell states in OSCC-GB.

Discovery of a glucocorticoid receptor (GR) activity signature correlates with immune cell infiltration in adrenocortical carcinoma

BackgroundAdrenocortical carcinoma (ACC) is a rare and highly aggressive endocrine malignancy, of which >40% present with glucocorticoid excess. Glucocorticoids and glucocorticoid receptor (GR) signaling have long been thought to suppress...

Prognostic Significance of Pretreatment Immune Cell Infiltration in Muscle Invasive Bladder Cancer Treated with Definitive Chemoradiation: Analysis of NRG RTOG 0524 and 0712

Chemoradiation therapy (CRT) is an organ conserving approach in the treatment of locally advanced bladder cancer. Chemoradiation is thought to potentially result in immunogenic stimulation, and bladder cancer is often a tumor with high immune cell infiltration. Thus, we aimed to profile the tumor immune microenvironment of bladder cancer and identify prognostic immune biomarkers for CRT response by profiling tumor samples from NRG/RTOG 0524 and 0712, two prospective trials of CRT in muscle invasive bladder cancer (MIBC). Pretreatment tissue samples from both trials were profiled using Cofactor Genomics ImmunoPrism, an RNA sequencing assay that uses gene expression profiles to quantify immune cell populations in the tumor microenvironment (TME). Differential gene expression was estimated for different immune cell type proportions across samples. Kaplan-Meier survival analysis and log rank tests were performed to evaluate differences in overall survival (OS) stratified by genes influenced by immune cell proportions or genes associated with immune response signatures. A total of 70 samples (43 from RTOG 0524 and 27 from RTOG 0712) underwent analysis using the ImmunoPrism assay. Immune cell proportions were as follows: CD8 T cells: median 1.2%, CD4 T cells: median 0.8%, Treg cells: median 9.2%, CD19 B cells: median 5.1%, M2 macrophages: median 0.8%, M1 macrophages: median 0%. Unbiased clustering based on gene expression profiles driven by immune cell proportions demonstrated two groups: cluster 1 with a low percentage of immune cells and shorter OS (median 31 months) and cluster 2 with a high percentage of immune cells and longer OS (median 101 months, p = 0.036). Higher expression of genes associated with T cell infiltration (CD8A and ICOS) was associated with improved OS (104 vs 35 months, p = 0.028, HR = 0.48 (0.25 - 0.94), p = 0.031) as was higher expression of IDO1, which is associated with the interferon gamma pathway (104 vs 35 months, p = 0.042, HR = 0.49 (0.24 - 0.99), p = 0.046). Bladder tumors have a wide range of immune cell infiltration in the TME. Increased immune cell proportions are prognostic for OS following CRT, as well as a higher expression of genes associated with T cell infiltration interferon gamma signaling. These findings have implications for the integration of immunotherapy in the definitive management of MIBC; and can be explored further in the ongoing NRG/SWOG 1806 trial.

Prediction of prognosis and immune landscape in cervical cancer based on heat shock protein-related genes

Objective: Heat shock proteins (HSPs) play key roles in the malignant transformation and progression of many tumors. However, the effectiveness of using HSP-related genes to predict the prognosis of patients with cervical cancer (CC) remains elusive. We aimed to delineate the prognosis and biological significance of HSP-related genes in CC. Methods: We collected the transcriptional and clinical data of CC patients from The Cancer Genome Atlas (TCGA) and searched for HSP-related genes in the literature. LASSO and univariate/multivariate Cox regression analyses were utilized to screen genes; 12 genes were found to be related to CC survival, and a prediction model was built. The effectiveness of the model was confirmed using TCGA and GEO, and it was found to be an independent predictor of CC. The nomogram is plotted. The prognostic model was further visualized using calibration curves, which showed good agreement with the predicted outcomes at 1-, 3, and 5 years. Results: We found that low-risk patients had higher immune cell infiltration and stronger immune function, and according to the immunophenoscore and TIDE scores, the low-risk group tended to respond more to immunotherapy. Additionally, we used the GDSC database to predict drug sensitivity in patients with different prognostic risks. Conclusion: In summary, we built a good model to help predict the prognosis of CC patients and provide a reference for personalized treatment and medication for different patients.

Construction of a Novel Disulfidptosis-Related lncRNA Prognostic Signature in Pancreatic Cancer.

Pancreatic cancer is a lethal, extremely aggressive gastrointestinal tumor with a poor prognosis and limited treatment alternatives. Disulfidptosis is a newly defined type of cell death with potential influence on cancer. Research on the association between disulfidptosis and pancreatic cancer is scarce.The expression data of disulfidptosis-related genes were downloaded from The Cancer Genome Atlas-Pancreatic Adenocarcinoma (TCGA). Disulfidptosis-related lncRNA signature (DRLS) was developed through the Cox and the least absolute shrinkage and selection operator (LASSO) analysis. Differences in enrichment functions, mutational landscape, immune microenvironment, and predicted therapeutic efficacy between high- and low-risk groups were assessed. Consensus clustering analysis was applied to identify the DRLS-related subtypes.Among 98 disulfidptosis-related lncRNAs, 5 lncRNAs were screened thus constructing a prognostic DRLS. DRLS showed high predictive accuracy and was an independent prognostic factor for pancreatic cancer. According to the risk scores calculated from the signature, samples were categorized into high- and low- risk groups. Overall, low-risk patients had a better prognosis, lower mutational occurrences, higher immune cell infiltration and more sensitivity to anti-tumor agents.The DRLS performed well in predicting prognosis and revealed intimate correlation with biological function, mutation status and immune infiltration landscape of pancreatic cancer, providing some insights for future research on the relationship between disulfidptosis and pancreatic cancer.

ANXA1 is identified as a key gene associated with high risk and T cell infiltration in primary sclerosing cholangitis

BackgroundPrimary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease, with unclear pathogenesis. Although immune disorders, especially T cell infiltration, are thought to play a vital role in PSC, the specific pathogenesis mechanisms remain incompletely understood. This study evaluated the potential key gene associated with the PSC pathogenesis and analyzed the associations of the key gene with prognosis and immune cell infiltration by combining bioinformatics analysis and experimental verification.MethodsTranscriptome data of PSC and normal human liver tissues (GSE159676) were obtained from the gene expression omnibus database. Differentially expressed genes (DEGs) were identified, and differences in biological states were analyzed. A protein–protein interaction (PPI) network was constructed. Hub genes were identified, and their expression was verified using transcriptome data of mice fed 0.1% 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) and Mdr2−/− mice (GSE179993, GSE80776), as well as by immunohistochemistry staining on clinical samples. The correlations between the key gene and other factors were evaluated by Pearson’s correlation coefficient. Immune cell infiltration into human liver (GSE159676) was analyzed by xCell and verified by immunofluorescence staining on PSC liver samples.ResultsOf the 185 DEGs identified, 113 were upregulated and 72 were downregulated genes in PSC. Genes associated with immune cell infiltration and fibrosis were significantly enriched in PSC. PPI network showed close interactions among DEGs. A module strongly associated with immune infiltration was identified, with annexin A1 (ANXA1) being the core gene. High expression of ANXA1 in PSC was confirmed in two public datasets and by immunohistochemistry staining on clinical samples. High ANXA1 expression was strongly associated with high-risk score for PSC. Also, ANXA1 expression was positively associated with chemokines and chemokine receptors and with the infiltration of immune cells, especially T cells, into liver with PSC. Immune infiltration, fibrosis, and cancer-related processes were markedly enriched in PSC with high expression of ANXA1.ConclusionANXA1 is a key gene associated with high risk and infiltration of immune cells, especially T cells, in PSC. These findings provide new insight into the key biomarker of PSC and suggest that targeting ANXA1 may be a valuable strategy for the treatment of PSC.

DNA damage repair profiling of esophageal squamous cell carcinoma uncovers clinically relevant molecular subtypes with distinct prognoses and therapeutic vulnerabilities

DNA damage repair (DDR) is a critical process that maintains genomic integrity and plays essential roles at both the cellular and organismic levels. Here, we aimed to characterize the DDR profiling of esophageal squamous cell carcinoma (ESCC), investigate the prognostic value of DDR-related features, and explore their potential for guiding personalized treatment strategies. We analyzed bulk and single-cell transcriptomics data from 377 ESCC cases from our institution and other publicly available cohorts to identify major DDR subtypes. The heterogeneity in cellular and functional properties, tumor microenvironment (TME) characteristics, and prognostic significance of these DDR subtypes were investigated using immunogenomic analysis and invitro experiments. Additionally, we experimentally validated a combinatorial immunotherapy strategy using syngeneic mouse models of ESCC. DDR alteration profiling enabled us to identify two distinct DDR subtypes, DDRactive and DDRsilent, which exhibited independent prognostic values in locoregional ESCC but not in metastatic ESCC. The DDRsilent subtype was characterized by an inflamed but immune-suppressed microenvironment with relatively high immune cell infiltration, abnormal immune checkpoint expression, T-cell exhaustion, and enrichment of cancer-related pathways. Moreover, DDR subtyping indicates that BRCA1 and HFM1 are robust and independent prognostic factors in locoregional ESCC. Finally, we proposed and verified that the concomitant triggering of GITR or blockade of BTLA with PD-1 blockade or cisplatin chemotherapy represents effective combination strategies for high-risk locoregional ESCC tumors. Our discovery of DDR-based molecular subtypes will enhance our understanding of tumor heterogeneity and have significant clinical implications for the therapeutic and management strategies of locoregional ESCC. This study was supported by the National Key R&D Program of China (2021YFC2501000, 2022YFC3401003), National Natural Science Foundation of China (82172882), the Beijing Natural Science Foundation (7212085), the CAMS Innovation Fund for Medical Sciences (2021-I2M-1-018, 2021-I2M-1-067), the Fundamental Research Funds for the Central Universities (3332021091), and the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (2019PT310027).

Comprehensive analysis of subtypes and risk model based on complement system associated genes in ccRCC

BackgroundImmune therapy is widely used in treating clear cell renal cell carcinoma (ccRCC), yet identifying patient subgroups that are expected to response remains challenging. As complement system can mediate immune effects, including the progression of tumors, a correlation between complement system and immune therapy may exist. MethodsBased on 11 complement system associated genes (CSAGs) identified from The Cancer Genome Atlas (TCGA), we performed unsupervised clustering and classified the tumors into two different complement system (CS) patterns. The clinical significance, tumor microenvironment (TME), functional enrichment, and immune infiltration were further analyzed. A novel scoring system named CSscore was developed based on the expression levels of the 11 CSAGs. ResultsTwo distinct CS patterns were identified, classified as Cluster1 and Cluster2, and Cluster1 showed poor clinical outcome. Further analysis of functional enrichment, immune cell infiltration, and genetic variation revealed that Cluster1 had high infiltration of TME immune cells, but also exhibited high immune escape. The novel prognostic model, CSscore could act as an independent prognostic factor and effectively predict patients' prognosis and distinguish the therapeutic efficacy of different immune treatment strategies. The pan-cancer analysis of the CSscore indicates its potential to be further generalized to other types of cancer. ConclusionsTwo distinct CS patterns were identified and were further analyzed in terms of infiltration of TME immune cells and immune escape, providing potential explanations for the impact on prognosis of ccRCC. Our CSscore prognostic model may offer a novel perspective in the management of ccRCC patients, and potentially other types of cancer as well.

The impact of mutational clonality in predicting the response to immune checkpoint inhibitors in advanced urothelial cancer

Immune checkpoint inhibitors (ICI) have revolutionized cancer treatment and can result in complete remissions even at advanced stages of the disease. However, only a small fraction of patients respond to the treatment. To better understand which factors drive clinical benefit, we have generated whole exome and RNA sequencing data from 27 advanced urothelial carcinoma patients treated with anti-PD-(L)1 monoclonal antibodies. We assessed the influence on the response of non-synonymous mutations (tumor mutational burden or TMB), clonal and subclonal mutations, neoantigen load and various gene expression markers. We found that although TMB is significantly associated with response, this effect can be mostly explained by clonal mutations, present in all cancer cells. This trend was validated in an additional cohort. Additionally, we found that responders with few clonal mutations had abnormally high levels of T and B cell immune markers, suggesting that a high immune cell infiltration signature could be a better predictive biomarker for this subset of patients. Our results support the idea that highly clonal cancers are more likely to respond to ICI and suggest that non-additive effects of different signatures should be considered for predictive models.

BAP1 mutations inhibit the NF-κB signaling pathway to induce an immunosuppressive microenvironment in uveal melanoma

BackgroundTumor immune microenvironment regulates the growth and metastasis of uveal melanoma (UM). This study aims to reveal the possible molecular mechanism of BRCA1-associated protein 1 (BAP1) mutations in affecting the tumor immune microenvironment in UM through mediating the nuclear factor-κB (NF-κB) signaling pathway.MethodsTCGA and cBioPortal databases jointly analyzed the genes with high mutation frequency in UM samples. Following survival analysis of UM patients, UM samples with BAP1 mutations were subjected to immune cell infiltration analysis. The signaling pathways associated with the mutated genes were screened by GSEA. Subsequently, the differential BAP1 expression was analyzed in the selected UM cell lines with wild type (WT) or mutant type (MUT) BAP1.ResultsBioinformatics analysis identified 12 genes mutated in the UM samples, while only BAP1 mutations were related to the prognosis of UM patients. UM patients with BAP1 mutations had higher immune cell infiltration. BAP1 mutations inhibited the NF-κB signaling pathway, suppressing the cytokine secretion and antigen presentation by macrophages. Rescue experiments confirmed that overexpressed NF-κB could reverse the effect of BAP1 mutations on the immunosuppressive microenvironment, thus suppressing the malignant phenotypes of UM cells.ConclusionBAP1 mutations may inhibit the NF-κB signaling pathway, repressing the cytokine secretion and antigen presentation by macrophages, which induces the immunosuppressive microenvironment, enhances the malignant phenotypes of UM cells and ultimately promotes the growth and metastasis of UM.

A novel immunogenic cell death-related genes signature for predicting prognosis, immune landscape and immunotherapy effect in hepatocellular carcinoma.

Immunogenic cell death (ICD) has emerged as a promising strategy to activate the adaptive immune response, modulate the tumor microenvironment (TME) and enhance the efficacy of immune therapy. However, the relationship between ICD and TME reprogramming in hepatocellular carcinoma (HCC) remains poorly understood. Transcriptional profiles and clinical spectrum of 486 HCC patients were obtained from TCGA and GEO databases. We utilized consensus clustering analysis to construct two distinct molecular subtypes and established an ICD-based scoring system (named ICD score) via WGCNA and LASSO Cox regression to predict the prognosis of the HCC cohort. Then we employed CIBERSORT and ESTIMATE methods to analyze the immune landscape of ICD score in HCC. Subsequently, the immunophenoscore (IPS) and tumor immune dysfunction and rejection (TIDE) analyses were performed to determine whether the ICD score could influence the immune therapeutic effect. Based on the ICD scoring system, a novel nomogram was generated to provide a numerical probability of HCC patients' overall survival (OS). We identified two independent ICD clusters (cluster A/B), and cluster B possessed a worse prognosis and higher immune cell infiltration. Using ICD scoring system, the HCC patients were divided into high- and low-ICD-score groups. Through integrative analyses, the high-ICD cohort owned advanced TNM stage, high pathologic grade and increased suppressive immune cell enrichment. We developed a nomogram containing the ICD score, demonstrating a high predictive accuracy with a C-index of 0.703. We further discovered that PSMD2 and PSMD14 could serve as ICD-associated prognostic biomarkers and therapeutic targets in HCC. The ICD score exhibits a high degree of reliability for predicting prognosis and may provide valuable guidance for the selection of immunotherapy for HCC patients. This novel scoring system enables the estimation of clinical immunotherapy response for HCC patients, offering new opportunities for personalized immunotherapy.