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Background: Integrin β5 (ITGB5) is a pivotal player in the pathogenesis of gastric cancer (GC). We aimed to explore the potential value of ITGB5 as a predictor of diagnosis and immunotherapy in gastric cancer. Methods: The expression of ITGB5 in GC was assessed using The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, and verified through quantitative polymerase chain reaction (qPCR) and immunohistochemistry. Kaplan-Meier curves were conducted to evaluate the prognostic significance. The immune cells infiltration, tumor mutational burden (TMB), and immunophenoscore (IPS) were examined using CIBERSORT, TIMER, and TISIDB. In addition, colony formation, scratch assays, and transwell assays were employed to determine the impact on tumor progression and metastasis. CD276 expression was detected by western blotting following the knockdown of ITGB5. ELISA was utilized to measure serum ITGB5 levels. Results: The expression of ITGB5 in GC tissue surpassed that in normal tissue, it might contribute to GC pathogenesis through pathways including PI3K-AKT, ECM-receptor interaction, and TGF-beta. The elevated ITGB5 expression is associated with poor prognosis in GC patients. In addition, a strong positive association between ITGB5 overexpression and the infiltration levels of macrophages and monocytes, and it significantly influenced immune response. Moreover, lower expression of ITGB5 was associated with better immunotherapy efficacy. Subsequent investigation demonstrated that silencing of ITGB5 suppressed the proliferation and migration of GC cell lines in vitro. ITGB5 expression was positively correlated with CD276 expression and the knockdown of ITGB5 resulted a notable decrease CD276 expression. Futhermore, a significantly high level of serum ITGB5 was observed in GC patients. The combined assessment of ITGB5, CEA, and CA19-9 improved the diagnostic accuracy. Conclusions: ITGB5 potentially serve as both a diagnostic biomarker and therapeutic target in managing GC. [ABSTRACT FROM AUTHOR]

Abstract Background Integrin β5 (ITGB5) is a pivotal player in the pathogenesis of gastric cancer (GC). We aimed to explore the potential value of ITGB5 as a predictor of diagnosis and immunotherapy in gastric cancer. Methods The expression of ITGB5 in GC was assessed using The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, and verified through quantitative polymerase chain reaction (qPCR) and immunohistochemistry. Kaplan-Meier curves were conducted to evaluate the prognostic significance. The immune cells infiltration, tumor mutational burden (TMB), and immunophenoscore (IPS) were examined using CIBERSORT, TIMER, and TISIDB. In addition, colony formation, scratch assays, and transwell assays were employed to determine the impact on tumor progression and metastasis. CD276 expression was detected by western blotting following the knockdown of ITGB5. ELISA was utilized to measure serum ITGB5 levels. Results The expression of ITGB5 in GC tissue surpassed that in normal tissue, it might contribute to GC pathogenesis through pathways including PI3K-AKT, ECM-receptor interaction, and TGF-beta. The elevated ITGB5 expression is associated with poor prognosis in GC patients. In addition, a strong positive association between ITGB5 overexpression and the infiltration levels of macrophages and monocytes, and it significantly influenced immune response. Moreover, lower expression of ITGB5 was associated with better immunotherapy efficacy. Subsequent investigation demonstrated that silencing of ITGB5 suppressed the proliferation and migration of GC cell lines in vitro. ITGB5 expression was positively correlated with CD276 expression and the knockdown of ITGB5 resulted a notable decrease CD276 expression. Futhermore, a significantly high level of serum ITGB5 was observed in GC patients. The combined assessment of ITGB5, CEA, and CA19-9 improved the diagnostic accuracy. Conclusions ITGB5 potentially serve as both a diagnostic biomarker and therapeutic target in managing GC.

Background: Dysregulation of RNA guanine-7 methyltransferase (RNMT) plays a crucial role in the tumor progression and immune responses. However, the detailed role of RNMT in pan-cancer is still unknown. Methods: Bulk transcriptomic data of pan-cancer were obtained from the Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), and Cancer Cell Line Encyclopedia (CCLE) databases. Single-cell transcriptomic and proteomics data of lung squamous cell carcinoma (LUSC) were analyzed in the Tumor Immune Single-cell Hub 2 (TISCH2) and Clinical Proteomic Tumor Analysis Consortium (CPTAC) databases, respectively. The correlation between RNMT expression and cancer prognosis was analyzed by Cox proportional hazards regression and Kaplan–Meier analyses. The correlation of RNMT expression with common immunoregulators, tumor mutation burden (TMB), microsatellite instability (MSI), mismatch repair (MMR), and DNA methyltransferase (DNMT) was analyzed. Additionally, the correlation between RNMT expression and immune infiltration level was evaluated. A total of 1287 machine learning combinations were used to construct prognostic models for LUSC. qRT-PCR and Western blot were used to validate the bioinformatics findings of RNMT upregulation in LUSC. Results: RNMT was widely expressed across different cancers, with significant correlation to prognosis in cancers such as kidney chromophobe (KICH) (p = 0.0033, HR = 7.12), liver hepatocellular carcinoma (LIHC) (p = 0.01, HR = 1.41), and others. Notably, RNMT participates in the regulation of the tumor microenvironment. RNMT expression positively correlated with immune cell expression (Spearman’s rank correlation, p

ATP citrate lyase (ACLY) is activated in various cancers, but its role in clear cell renal cell carcinoma (ccRCC) remains poorly understood. Herein, we investigated the prognostic role and potential mechanism of ACLY in ccRCC. The expression profile of ACLY in ccRCC was explored using Gene Expression Profiling Interactive Analysis 2 (GEPIA2), Gene Expression Omnibus (GEO), UALCAN and western blotting assays. The prognosis was investigated using immunohistochemistry (IHC) and Kaplan–Meier plotter assays. The relationship with immune infiltration was further evaluated using Tumor Immune Estimation Resource 2 (TIMER2) and Tumor Immune System Interactions and DrugBank (TISIDB) databases, respectively. Further biological function of ACLY in ccRCC pathogenesis was explored using in vitro experiments. ACLY level was higher in ccRCC than adjacent kidney tissues, and Kaplan–Meier survival analysis showed ACLY mRNA or protein were predictors of poor prognosis in ccRCC patients. Importantly, we reported for the first time that ACLY gene expression was significantly correlated with numerous immune cells and immune inhibitors in ccRCC. ACLY inhibition significantly impaired cell proliferation, induced cell apoptosis, attenuated cell migration, decreased lipid droplets formation, and suppressed epithelial-mesenchymal transition (EMT) of ccRCC. Moreover, these effects might be acted through mammalian target of rapamycin complex 1 (mTORC1) pathway. Collectively, ACLY was not only implicated in ccRCC tumorigenesis and progression, but also potentially interacted with immune infiltration and mTORC1 pathway. Our findings may provide a novel therapeutic strategy by targeting ACLY for ccRCC treatment.

Abstract Background One-third of diffuse large B-cell lymphoma (DLBCL) patients suffer relapse after standard treatment. Eukaryotic initiation factor 3a (eIF3a) is a key player in the initial stage of translation, which has been widely reported to be correlated with tumorigenesis and therapeutic response. This study aimed to explore the biological role of eIF3a, evaluate its prognostic and therapeutic potential in DLBCL. Methods RNA-seq datasets from GEO database were utilized to detect the expression and prognostic role of eIF3a in DLBCL patients. Protein level of eIF3a was estimated by western blot and immunohistochemical. Next, DLBCL cells were transfected with lentiviral vector either eIF3a-knockdown or empty to assess the biological role of eIF3a. Then, samples were divided into 2 clusters based on eIF3a expression and differentially expressed genes (DEGs) were identified. Function enrichment and mutation analysis of DEGs were employed to detect potential biological roles. Moreover, we also applied pan-cancer and chemosensitivity analysis for deep exploration. Results eIF3a expression was found to be higher in DLBCL than healthy controls, which was associated with worse prognosis. The expression of eIF3a protein was significantly increased in DLBCL cell lines compared with peripheral blood mononuclear cells (PBMCs) from healthy donors. eIF3a knockdown inhibited the proliferation of DLBCL cells and the expression of proliferation-related proteins and increase cell apoptosis rate. Besides, 114 DEGs were identified which had a close linkage to cell cycle and tumor immune. eIF3a and DEGs mutations were found to be correlated to chemosensitivity and vital signal pathways. Pan-cancer analysis demonstrated that high eIF3a expression was associated with worse prognosis in several tumors. Moreover, eIF3a expression was found to be related to chemosensitivity of several anti-tumor drugs in DLBCL, including Vincristine and Wee1 inhibitor. Conclusions We firstly revealed the high expression and prognostic role of eIF3a in DLBCL, and eIF3a might promote the development of DLBCL through regulating cell proliferation and apoptosis. eIF3a expression was related to immune profile and chemosensitivity in DLBCL. These results suggest that eIF3a could serve as a potential prognostic biomarker and therapeutic target in DLBCL.

Prostate cancer (PCa) currently ranks second in male tumor mortality. Targeting immune checkpoint in tumor as immunotherapy is a new direction for tumor treatment. However, targeting PD-1/PD-L1 and CTLA4 to treat PCa has poor immunotherapeutic efficacy because PCa is known as a cold tumor. Understanding the mechanism of immunosuppression in PCa can promote the use of immunotherapy to treat PCa. ELAVL1 is highly expressed in many tumors, participates in almost all tumor biological activities and is an oncogene. ELAVL1 is also involved in the development and differentiation of T and B lymphocytes. However, the relationship between ELAVL1 and tumor immunity has not yet been reported. In recent years, ELAVL1 has been shown to regulate downstream targets in an m6A -dependent manner. PD-L1 has been shown to have m6A sites in multiple tumors that are regulated by m6A. In this study, ELAVL1 was highly expressed in PCa, and PCa with high ELAVL1 expression is immunosuppressive. Knocking down ELAVL1 reduced PD-L1 expression in PCa. Moreover, PD-L1 was shown to have an m6A site, and its m6A level was upregulated in PCa. ELAVL1 interacts with PD-L1 mRNA and promotes PD-L1 RNA stability via m6A, ultimately inhibiting the infiltration of CD4-positive T cells. In addition, androgen receptor (AR) was shown to be regulated with ELAVL1, and knocking down AR could also affect the expression of PD-L1. Therefore, ELAVL1 can directly or indirectly regulate the expression of PD-L1, thereby affecting the infiltration of CD4-positive T cells in PCa and ultimately leading to immune suppression.

Background: One-third of diffuse large B-cell lymphoma (DLBCL) patients suffer relapse after standard treatment. Eukaryotic initiation factor 3a (eIF3a) is a key player in the initial stage of translation, which has been widely reported to be correlated with tumorigenesis and therapeutic response. This study aimed to explore the biological role of eIF3a, evaluate its prognostic and therapeutic potential in DLBCL. Methods: RNA-seq datasets from GEO database were utilized to detect the expression and prognostic role of eIF3a in DLBCL patients. Protein level of eIF3a was estimated by western blot and immunohistochemical. Next, DLBCL cells were transfected with lentiviral vector either eIF3a-knockdown or empty to assess the biological role of eIF3a. Then, samples were divided into 2 clusters based on eIF3a expression and differentially expressed genes (DEGs) were identified. Function enrichment and mutation analysis of DEGs were employed to detect potential biological roles. Moreover, we also applied pan-cancer and chemosensitivity analysis for deep exploration. Results: eIF3a expression was found to be higher in DLBCL than healthy controls, which was associated with worse prognosis. The expression of eIF3a protein was significantly increased in DLBCL cell lines compared with peripheral blood mononuclear cells (PBMCs) from healthy donors. eIF3a knockdown inhibited the proliferation of DLBCL cells and the expression of proliferation-related proteins and increase cell apoptosis rate. Besides, 114 DEGs were identified which had a close linkage to cell cycle and tumor immune. eIF3a and DEGs mutations were found to be correlated to chemosensitivity and vital signal pathways. Pan-cancer analysis demonstrated that high eIF3a expression was associated with worse prognosis in several tumors. Moreover, eIF3a expression was found to be related to chemosensitivity of several anti-tumor drugs in DLBCL, including Vincristine and Wee1 inhibitor. Conclusions: We firstly revealed the high expression and prognostic role of eIF3a in DLBCL, and eIF3a might promote the development of DLBCL through regulating cell proliferation and apoptosis. eIF3a expression was related to immune profile and chemosensitivity in DLBCL. These results suggest that eIF3a could serve as a potential prognostic biomarker and therapeutic target in DLBCL. [ABSTRACT FROM AUTHOR]

Purpose: Tumor metastasis significantly impacts the prognosis of non-small cell lung cancer (NSCLC) patients, with lymph node (LN) metastasis being the most common and early form of spread. With the development of adjuvant immunotherapy, increasing attention has been paid to the tumor-draining lymph nodes（TDLN) in early-stage NSCLC, especially tumor-metastatic lymph nodes, which provides poor prognostic information but has potential benefits in adjuvant treatment. Methods: We showed the remodeled immune environment in TDLNs through using TCR-seq to analyse 24 primary lung cancer tissues and 134 LNs from 24 lung cancer patients with or without LN metastasis. Additionally, we characterized the spatial profiling of immunocytes and tumor cells in TDLNs and primary tumor sites through using multi-IHC. Results: We found the remodeled immune environment in TDLNs through analyzing primary lung cancer tissues and LNs from NSCLC patients with or without LN metastasis. Considering the intricate communication between tumor and immunocytes, we further subdivided TDLNs, revealing that metastasis-negative LNs from LN-metastatic patients (MNLN) exhibited greater immune activation, exhaustion, and memory in comparison to both metastasis-positive LNs (MPLN) and TDLNs from non-LN-metastatic patients (NMLN). Conclusions: Our data indicate that LN metastasis facilitated tumor-specific antigen presentation in TDLNs and induces T cell priming, while existing tumor cells generate an immune-suppressive environment in MPLNs through multiple mechanisms. These findings contribute to a comprehensive understanding of the immunological mechanisms through which LN metastasis influences tumor progression and plays a role in immunotherapy for NSCLC patients. [ABSTRACT FROM AUTHOR]

The emerging evidence suggested that senescence regulator genes might involve in the progression of clear cell renal cell cancer, while the details remain larger unknown. In this work, we comprehensively investigated the function of senescence regulator genes in ccRCC across multi omics and validated the findings with experiments. ccRCC patients could be divided into SPCS1 (normal aging group) and SPCS2 (Aging disorder group). SPCS2, an aggressive subtype, comprised higher clinical stage and worse prognosis, which indicated activated oncogenic signaling pathway and metabolic signatures to prompt cancer expansion. SPCS2 subgroup owned immunocompromised status, which induced immune dysfunction and low ICI therapy response. In conclusion, senescence regulator-related signature could modify functional pathways and tumor immune microenvironment by genome mutation and pathway interaction. Rationale: The emerging evidence suggested that senescence regulator genes were involved in multi cancers, which may be utilized as new targets for cancers. However, the dysregulation and clinical impact of senescence regulator genes in clear cell renal cell cancer (ccRCC) were still in foggy. Methods: Using multiomics data from TCGA-KIRC and other datasets, we comprehensively investigated the function of senescence regulator genes in ccRCC. ccRCC patients could be remodeled into 2 significant different groups basing on senescence regulators expression: senescence-pattern cancer subtype1 (SPCS1) and subtype2 (SPCS2). We further explored clinical characteristics, functional analysis, tumor immune microenvironment, immunotherapy response, genomic mutation and drug sensitivity between the 2 subtypes. Besides, senescence-pattern related risk model was established to determine the patient's prognosis of ccRCC. Finally, the overview of MECP2 function was investigated in multi cancers. Results: ccRCC patients could be divided into SPCS1 (normal aging group) and SPCS2 (Aging disorder group). The 2 subtypes showed significant different clinical characteristics and biological process in ccRCC. SPCS2, an aggressive subtype, comprised higher clinical stage and worse prognosis of ccRCC patients. SPCS2 subtype indicated activated oncogenic signaling pathway and metabolic signatures to prompt cancer expansion. SPCS2 subgroup owned immunocompromised status, which induced immune dysfunction and low ICI therapy response. The genome-copy numbers of SPCS2, including arm-gain and arm-loss was significantly more frequent than SPCS1. In addition, the 2 subtypes argue contrasting drug sensitivity profiles in clinical specimens and matched cell lines. Finally, we constructed a prognostic risk model consisted of each subtype's leading biomarkers, which exerted a satisfied performance for ccRCC patients. Conclusion: Senescence regulator-related signature could modify functional pathways and tumor immune microenvironment by genome mutation and pathway interaction. Senescence regulator-related molecular subtype strengthen the understanding of ccRCC' characterization and guide clinical treatment. Targeting senescence regulators may be regard as a proper way in ccRCC. [ABSTRACT FROM AUTHOR]

Gastric cancer is a highly immunogenic malignancy. Immune tolerance facilitated by myeloid-derived suppressor cells (MDSCs) has been implicated in gastric cancer resistance mechanisms. The potential role of APE1 in regulating gastric cancer metastasis by targeting MDSCs remains uncertain. In this study, the plasmid Plxpsp-mGM-CSF was used to induce high expression of granulocyte-macrophage colony-stimulating factor (GM-CSF) in GES-1 cells. For tumor transplantation experiments, AGS, AGS+GM-CSF and AGS+GM-CSF-siAPE1 cell lines were established by transfection, followed by subcutaneous implantation of tumor cells. MDSCs, Treg cells, IgG, CD3 and CD8 levels were assessed. Transfection with siAPE1 significantly inhibited tumor growth compared to the AGS+GM-CSF group. APE1 gene knockdown modulated the immune system in gastric cancer mice, characterized by a decrease in MDSCs and an increase in Treg cells, IgG, CD3 and CD8. In addition, APE1 gene knockdown resulted in decreased levels of pro-MDSC cytokines (HGF, CCL5, IL-6, CCL12). Furthermore, APE1 gene knockdown inhibited proliferation, migration and invasion of AGS and MKN45 cells. AGS-GM-CSF cell transplantation increased MDSC levels and accelerated tumor growth, whereas APE1 knockdown reduced MDSC levels, inhibited tumor growth and attenuated inflammatory infiltration in gastric cancer tissues. Strategies targeting the APE1/MDSC axis offer a promising approach to the prevention and treatment of gastric cancer, providing new insights into its management. [ABSTRACT FROM AUTHOR]

Metal complexes represented by platinum complexes play a very important role in cancer treatment due to their diverse chemical structures and anti‐tumor activities. Recently, ferroptosis has emerged as a newly occurring cell death form in the anti‐tumor process. It has been reported that metal complexes could inhibit the proliferation and metastasis of tumors and combat chemotherapy resistance by targeting ferroptosis. In this review, we briefly describe ferroptosis as a fundamental process for tumor suppression and triggering anti‐tumor immune responses. We summarize recent developments on metal complexes that induce ferroptosis. Finally, we outline the prospects for the application of metal complexes to the treatment of tumors based on ferroptosis and the associated problems that need to be solved, and discussed other potential research directions of metal complexes. [ABSTRACT FROM AUTHOR]

Xing Wang,1,2,* Xiaojing Yang,1,3,* Yiming Zhang,1 Afei Guo,1 Suju Luo,1 Meng Xiao,1 Lu Xue,1 Guohui Zhang,2 Huiping Wang1 1Department of Dermatovenereology, Tianjin Medical University General Hospital, Tianjin, People’s Republic of China; 2Department of Dermatovenereology, Baotou Central Hospital, Baotou City, Inner Mongolia, People’s Republic of China; 3Department of Dermatovenereology, the First Affiliated Hospital of Hebei North University, Zhangjiakou, Hebei, People’s Republic of China*These authors contributed equally to this workCorrespondence: Huiping Wang; Guohui Zhang, Email huiping1208@163.com; 1259314465@qq.comIntroduction: Skin cutaneous melanoma is becoming more dangerous since it has a poor prognosis and is resistant to treatment. Previous research has shown that lncRNAs and fatty acid metabolism are essential for numerous biological activities. There are no studies on the relationship between fatty acid metabolism-Related lncRNAs and skin cutaneous melanoma.Methods and Results: In order to better understand the prognosis and survival of SKCM patients, we investigated the significance of lncRNAs related to fatty acid metabolism. In this work, we looked at the fatty acid metabolism genes and lncRNAs expression patterns. On the basis of lncRNAs associated with fatty acid metabolism, a nomogram and a prognosis prediction model were created. Based on the profile of lncRNAs associated with fatty acid metabolism, functional and pharmacological sensitivity investigations were also carried out. We also looked at the connection between immunotherapy and the immune response. The findings demonstrated that a risk score model based on 11 essential lncRNAs for fatty acid metabolism may discriminate between the clinical condition of SKCM and more accurately predict prognosis and survival. We conducted quantitative reverse transcription polymerase-chain reaction (RT-PCR) to verify the model.Conclusion: These important lncRNAs further showed a strong association with the tumor immune system, and these important lncRNAs also showed a connection between SKCM and chemotherapeutic treatment sensitivity. Our research strives to provide fresh viewpoints and innovative approaches to the treatment and administration of SKCM.Keywords: skin cutaneous melanoma, lncRNA, fatty acid metabolism, bioinformatics, tumor immune

Objectives: Rapidly growing evidence suggests that immune cells play a key role in determining tumor progression. Tumor cells are surrounded by a microenvironment composed of different cell populations including immune cells. The cross talk between tumor cells and the neighboring microenvironment is an important factor to take into account while designing tumor therapies. Despite significant advances in immunotherapy strategies, a relatively small proportion of patients have successfully responded to them. Therefore, the search for safe and efficient drugs, which could be used alongside conventional therapies to boost the immune system against tumors, is an ongoing need. In the present work, the modulatory effects of melatonin on different components of tumor immune microenvironment are reviewed. Methods: A thorough literature review was performed in PubMed, Scopus, and Web of Science databases. All published papers in English on tumor immune microenvironment and the relevant modulatory effects of melatonin were scrutinized. Results: Melatonin modulates macrophage polarization and prevents M2 induction. Moreover, it prevents the conversion of fibroblasts into cancer-associated fibroblasts (CAFs) and prevents cancer cell stemness. In addition, it can affect the payload composition of tumor-derived exosomes (TEXs) and their secretion levels to favor a more effective anti-tumor immune response. Melatonin is a safe molecule that affects almost all components of the tumor immune microenvironment and prevents them from being negatively affected by the tumor. Conclusion: Based on the effects of melatonin on normal cells, tumor cells and microenvironment components, it could be an efficient compound to be used in combination with conventional immune-targeted therapies to increase their efficacy. [ABSTRACT FROM AUTHOR]

Background: Kidney renal clear cell carcinoma (KIRC), with low survival rate, is the most frequent subtype of renal cell carcinoma. Recently, more and more studies indicate that cuproptosis-related genes (CRGs) and long non-coding RNAs (lncRNAs) play a vital role in the occurrence and development of many types of cancers. However, the roles of cuproptosis-related lncRNAs (CRlncRNAs) in the KIRC was uncertain. Results: In our study, CRlncRNAs were obtained by coexpression between differentially expressed and prognostic CRGs and differentially expressed and prognostic lncRNAs, and an 8-CRlncRNAs (AC007743.1, AC022915.1, AP005136.4, APCDD1L-DT, HAGLR, LINC02027, MANCR and SMARCA5-AS1) risk model was established according to least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression. This risk model could differentiate immune cell infiltration, immune function and gene mutation. Conclusions: This 8-CRlncRNAs risk model may be promising for the clinical prediction of prognoses, tumor immune, immunotherapy response and chemotherapeutic response in KIRC patients.

N1-methyladenosine (m1A) modification is a crucial post-transcriptional regulatory mechanism of messenger RNA (mRNA) in living organisms. Few studies have focused on analysis of m1A regulators in lower-grade gliomas (LGG). We employed the Nonnegative Matrix Factorization (NMF) technique on The Cancer Genome Atlas (TCGA) dataset to categorize LGG patients into 2 groups. These groups exhibited substantial disparities in terms of both overall survival (OS) and levels of infiltrating immune cells. We collected the significantly differentially expressed immune-related genes between the 2 clusters, and performed LASSO regression analysis to obtain m1AScores, and established an m1A-related immune-related gene signature (m1A-RIGS). Next, we categorized all patients with LGG into high- and low-risk subgroups, predictive significance of m1AScore was confirmed by conducting univariate/multivariate Cox regression analyses. Additionally, we confirmed variations in immune-related cells and ssGSEA and among the high-/low-risk subcategories in the TCGA dataset. Finally, our study characterized the effects of MSR1 and BIRC5 on LGG cells utilizing Edu assay and flow cytometry to explore the effects of modulation of these genes on glioma. The results of this study suggested that m1A-RIGS may be an excellent prognostic indicator for patients with LGG, and could also promote development of novel immune-based treatment strategies for LGG. Additionally, BIRC5 and MSR1 may be potential therapeutic targets for LGG.

Background: Prostate cancer (PCa) ranks as the second most prevalent malignancy among males on a global scale. Accumulating evidence suggests that inflammation has an intricate relationship with tumorigenesis, tumor progression and tumor immune microenvironment. However, the overall impact of inflammation-related genes on the clinical prognosis and tumor immunity in PCa remains unclear. Methods: Machine learning methods were utilized to construct and validate a signature using The Cancer Genome Atlas (TCGA) for training, while the Memorial Sloan Kettering Cancer Center (MSKCC) and GSE70769 cohorts for independent validation. The efficacy of the signature in predicting outcomes and its clinical utility were assessed through a series of investigations encompassing in vitro experiments, survival analysis, and nomogram development. The association between the signature and precision medicine was explored via tumor immunity, genomic heterogeneity, therapeutic response, and molecular docking analyses, using bulk and single-cell RNA-sequencing data. Results: We identified 7 inflammation-related genes with prognostic significance and developed an inflammation-related prognostic signature (IRPS) with 6 genes. Furthermore, we demonstrated that both the IRPS and a nomogram integrating risk score and pathologic T stage exhibited excellent predictive ability for the survival outcomes in PCa patients. Moreover, the IRPS was found to be significantly associated with the tumor immune, genomic heterogeneity, therapeutic response, and drug selection. Conclusion: IRPS can serve as a reliable predictor for PCa patients. The signature may provide clinicians with valuable information on the efficacy of therapy and help personalize treatment for PCa patients.

Background: Reprogramming in glutamine metabolism is a hallmark of cancers, while its role in cutaneous melanoma has not been studied at great length. Methods: Here, we constructed a glutamine metabolism-related prognostic signature in cutaneous melanoma with a variety of bioinformatics methods according to the glutamine metabolism regulatory molecules. Moreover, experimental verification was carried out for the key gene. Results: We have identified two subgroups of cutaneous melanoma patients, each with different prognoses, immune characteristics, and genetic mutations. GOT2 was the most concerned key gene among the model genes. We verified its role in promoting tumor cell proliferation by CCK-8 and clone formation assays. Conclusion: Our study cast new light on the prognosis of cutaneous melanoma, and the internal mechanism regulating glutamine metabolism of GOT2 may provide a new avenue for treating the cutaneous melanoma disease precisely. [ABSTRACT FROM AUTHOR]

Lactate dehydrogenase (LDH) is a crucial glycolytic enzyme which mediates the metabolic plasticity of cancer cells, however its clinical significance in renal cell car- cinoma (RCC) is poorly understood. Herein, we examined the prognostic significance of the two primary components of LDH, i.e., LDHA and LDHB, in clear cell RCC (ccRCC) patients and further explored their association with immune infiltration in ccRCC. In this study, the expression levels of LDHA and LDHB were examined in ccRCC and adjacent normal tissues by Gene Expression Profiling Interactive Analysis 2 (GEPIA2), UALCAN, and western blotting (WB) analyses, and their prognostic values were estimated in 150 ccRCC and 30 adjacent normal tissues by immunohistochemistry (IHC) analysis. The relationship to immune infiltration of LDHA and LDHB genes was further investigated using tumor immune estimation resource 2 (TIMER2) and Tumor-Immune System Interactions and DrugBank (TISIDB) databases, respectively. Public databases and WB analyses demonstrated higher LDHA and lower LDHB in ccRCC than in non-tumor tissues. IHC analysis revealed that LDHA and LDHB expression profiles were significantly associated with tumor grade, stage, size, and overall survival (OS). Univariate survival analysis displayed that high grade, advanced stage, large tumor, metastasis, high LDHA, and low LDHB expression were significantly associated with a poorer OS, and multivariate analysis revealed tumor stage and LDHB were identified as independent predictors for OS in patients with ccRCC. Further TIMER2 and TISIDB analyses demonstrated that LDHA and LDHB expression was significantly related to multiple immune cells and immune inhibitors in over 500 ccRCC patients. These findings revealed that LDHB was an independent favorable predictor, and LDHA and LDHB correlated with tumor immune infiltrates in ccRCC patients, which indicated LDHA/LDHB could be implicated in the tumorigenesis of ccRCC and might be potential therapeutic targets for patients with ccRCC. [ABSTRACT FROM AUTHOR]

Abstract Background The immunological checkpoint known as Inducible T Cell Costimulatory Factor (ICOS, Cluster of Differentiation, CD278) is activated and expressed on T cells. Both somatic cells and antigen-presenting cells expressed its ligand, ICOSL (including tumor cells in the tumor microenvironment).It is important for immunosuppression. Uncertainty surrounds the function of ICOS in tumor immunity. Methods Several bioinformatics techniques were employed by us to thoroughly examine the expression and prognostic value of ICOS in 33 cancers based on data collected from TCGA and GTEx. In addition, ICOS was explored with pathological stage, tumor-infiltrating cells, immune checkpoint genes, mismatch repair (MMR) genes, DNA methyltransferases (DNMTs), microsatellite instability (MSI),and tumor mutation burden (TMB).In addition,To ascertain the level of ICOS expression in various cells, qRT-PCR was employed. Results The findings revealed that ICOS expression was up regulation in most cancer types. The high expression of ICOS in tumor samples was related to the poor prognosis of UVM and LGG; The positive prognosis was boosted by the strong expression of ICOS in OV, SARC, SKCM, THYM, UCEC, and HNSC. The result is that the expression of malignancy was revealed by the immune cells’ invasion.profile of ICOS in different types of cancer. Different ways that ICOS expression is connected to immune cell infiltration account for variations in patient survival. Additionally, the TMB, MSI, MMR, and DNMT genes as well as ICOS expression are linked in many cancer types.The results of PCR showed that it is highly expressed in gastric, breast, liver and renal cell carcinoma cell lines compared with normal cells. Conclusion This study suggests that ICOS may be a potential tumor immunotherapy target and prognostic marker.

Chengxuan Liu,1 Weijian Xiong,1 Jing Song,2 Xiaoqin Ouyang,1 Yang Fu3 1Department of Nephrology, Chongqing Traditional Chinese Medicine Hospital, Chongqing, People’s Republic of China; 2Molecular Medicine and Cancer Research Centre, Chongqing Medical University, Chongqing, People’s Republic of China; 3Department of Rehabilitation, Chongqing Traditional Chinese medicine Hospital, Chongqing, People’s Republic of ChinaCorrespondence: Yang Fu, Department of Rehabilitation, Chongqing Traditional Chinese Medicine Hospital, No. 6 Panxi Branch Road, Jiangbei District, Chongqing, 400021, People’s Republic of China, Email fuyang@stu.cdutcm.edu.cnIntroduction: The overall survival of patients with high-stage clear cell renal carcinoma (ccRCC) is poor. However, promising molecular-level prognostic marker is still lacking to date.Methods: We systematically evaluated the prognostic potential of immune-related long non-coding RNAs (lncRNAs) in ccRCC. The expressions of lncRNAs were validated in clinical tissues of ccRCC. Functional experiments were performed to investigate the role of lncRNAs in ccRCC.Results: Eight hundred and ninety-three lncRNAs were differentially expressed in ccRCC and compared with normal controls and were screened out using three independent cohorts. Among them, 290 immune-related lncRNAs were identified. We identified a seven-lncRNA signature (LINC01270, FIRRE, RP11-37B2.1, RP11-253I19.3, RP11-438L19.1, RP11-504P24.9, and CTB-41I6.1) associated with the overall survival of late-stage ccRCC patients. Further multivariate Cox analysis using clinical factors as covariates showed that our lncRNA signature was an independent biomarker in training (P < 0.001, Log rank test) and validation cohorts (P = 0.003). The seven lncRNAs were closely related to the major targets (PD-1, PD-L1, and CTLA4) of immune checkpoint blockade drugs, implying that they may have potential value in predicting immunotherapy response. The seven lncRNAs may play an important role in tumor-infiltrating immune cells (eg, T/B cells) and tumor progression through regulating the binding of protein receptors/complexes, as revealed by functional analysis. qRT-PCR showed that LINC01270 was upregulated in ccRCC tissues (n=20) compared with paired normal samples. Functional experiments showed that LINC01270 silencing inhibited the proliferation, invasion, and migration of ccRCC cells.Discussion: In summary, the seven-lncRNA signature has great potential in prognosis for patients with late-stage ccRCC, which could be a novel clinical biomarker. LINC01270 could be a novel therapeutic target of ccRCC.Keywords: long non-coding RNA FIRRE, prognosis, renal cell carcinoma, tumor immune

Colorectal cancer is one of the malignant tumors with the highest mortality rate in the world. Survival rates vary significantly among patients at various stages of the disease. A biomarker capable of early diagnosis is required to facilitate the early detection and treatment of colorectal cancer. Human endogenous retroviruses (HERVs) are abnormally expressed in various diseases, including cancer, and have been involved in cancer development. Real-time quantitative PCR was used to detect the transcript levels of HERV-K(HML-2) gag, pol, and env in colorectal cancer to systematically investigate the connection between HERV-K(HML-2) and colorectal cancer. The results showed that HERV-K(HML-2) transcript expression was significantly higher than healthy controls and was consistent at the population and cell levels. We also used next-generation sequencing to identify and characterize HERV-K(HML-2) loci that were differentially expressed between colorectal cancer patients and healthy individuals. The analysis revealed that these loci were concentrated in immune response signaling pathways, implying that HERV-K impacts the tumor-associated immune response. Our results indicated that HERV-K might serve as a screening tumor marker and a target for tumor immunotherapy in colorectal cancer. [ABSTRACT FROM AUTHOR]

Introduction: Hepatocellular carcinoma (HCC) has a high mortality rate worldwide. The dysregulation of RNA splicing is a major event leading to the occurrence, progression, and drug resistance of cancer. Therefore, it is important to identify new biomarkers of HCC from the RNA splicing pathway. Methods: We performed the differential expression and prognostic analyses of RNA splicing-related genes (RRGs) using The Cancer Genome Atlas-liver hepatocellular carcinoma (LIHC). The International Cancer Genome Consortium (ICGC)-LIHC dataset was used to construct and validate prognostic models, and the PubMed database was used to explore genes in the models to identify new markers. The screened genes were subjected to genomic analyses, including differential, prognostic, enrichment, and immunocorrelation analyses. Single-cell RNA (scRNA) data were used to further validate the immunogenetic relationship. Results: Of 215 RRGs, we identified 75 differentially expressed prognosis-related genes, and a prognostic model incorporating thioredoxin like 4A (TXNL4A) was identified using least absolute shrinkage and selection operator regression analysis. ICGC-LIHC was used as a validation dataset to confirm the validity of the model. PubMed failed to retrieve HCC-related studies on TXNL4A. TXNL4A was highly expressed in most tumors and was associated with HCC survival. Chisquared analyses indicated that TXNL4A expression positively correlated positively with the clinical features of HCC. Multivariate analyses revealed that high TXNL4A expression was an independent risk factor for HCC. Immunocorrelation and scRNA data analyses indicated that TXNL4A was correlated with CD8 T cell infiltration in HCC. Conclusion: Therefore, we identified a prognostic and immune-related marker for HCC from the RNA splicing pathway. [ABSTRACT FROM AUTHOR]

Abstract Background N7-Methylguanosine (m7G) and long non-coding RNAs (lncRNAs) have been widely studied in cancer and have been found to be useful for assessing tumor progression. However, the role of m7G-related lncRNAs in lung squamous cell carcinoma (LUSC) remains unclear. Thus, it is crucial to identify m7G-associated lncRNAs with definitive prognostic value. This study aimed to investigate the prognostic value, correlation with tumor mutation burden, and impact on the tumor immune microenvironment of m7G-related lncRNAs in LUSC. Methods LUSC transcriptome data and clinical data were downloaded from The Cancer Genome Atlas, and an m7G-related lncRNA-mRNA co-expression network was constructed using Pearson’s correlation analysis. Cox regression analyses were used to determine a risk model for m7G-associated lncRNAs with prognostic value. The risk signature was verified using the Kaplan–Meier method, receiver operating characteristic curve analysis, and principal component analysis. A nomogram based on risk scores and clinical characteristics was then developed. Gene set enrichment analysis was used for functional annotation to analyze the risk signature. The association among the risk signature, tumor mutational burden, and tumor-infiltrating immune cells was then analyzed. RT-qPCR was used to investigate the expression of 6 m7G-related lncRNAs in LUSC cells. The cytological function of SRP14-AS1 was verified by wound-healing assay and transwell assay. Results A total of 293 m7G-related lncRNAs were identifed, 27 candidate m7G-related lncRNAs were signifcantly associated with overall survival (OS). Six of these lncRNAs (CYP4F26P, LINC02178, MIR22HG, SRP14-AS1, TMEM99, PTCSC2) were selected for establishment of the risk model. The OS of patients in the low-risk group was higher than that of patients in the high-risk group (p

Yin-Yang 1 (YY1) is a member of the GLI-Kruppel family of zinc finger proteins and plays a vital dual biological role in cancer as an oncogene or a tumor suppressor during tumorigenesis and tumor progression. The tumor microenvironment (TME) is identified as the "soil" of tumor that has a critical role in both tumor growth and metastasis. Many studies have found that YY1 is closely related to the remodeling and regulation of the TME. Herein, we reviewed the expression pattern of YY1 in tumors and summarized the function and mechanism of YY1 in regulating tumor angiogenesis, immune and metabolism. In addition, we discussed the potential value of YY1 in tumor diagnosis and treatment and provided a novel molecular strategy for the clinical diagnosis and treatment of tumors. [ABSTRACT FROM AUTHOR]

Oncolytic viruses are a type of virus that infects and kills tumor cells more than other cells. They act as "immune modification platforms" that express immune checkpoint inhibitors, tumor antigens, cytokines, and T cell engagers. They can be engineered or tested to selectively multiply and kill cancer cells. Targeting strategies include deleting the gene for the virulence factor and using abnormal signaling pathways in cancer cells to stop them from multiplying and becoming lethal. [ABSTRACT FROM AUTHOR]

Background: The immunological checkpoint known as Inducible T Cell Costimulatory Factor (ICOS, Cluster of Differentiation, CD278) is activated and expressed on T cells. Both somatic cells and antigen-presenting cells expressed its ligand, ICOSL (including tumor cells in the tumor microenvironment).It is important for immunosuppression. Uncertainty surrounds the function of ICOS in tumor immunity. Methods: Several bioinformatics techniques were employed by us to thoroughly examine the expression and prognostic value of ICOS in 33 cancers based on data collected from TCGA and GTEx. In addition, ICOS was explored with pathological stage, tumor-infiltrating cells, immune checkpoint genes, mismatch repair (MMR) genes, DNA methyltransferases (DNMTs), microsatellite instability (MSI),and tumor mutation burden (TMB).In addition,To ascertain the level of ICOS expression in various cells, qRT-PCR was employed. Results: The findings revealed that ICOS expression was up regulation in most cancer types. The high expression of ICOS in tumor samples was related to the poor prognosis of UVM and LGG; The positive prognosis was boosted by the strong expression of ICOS in OV, SARC, SKCM, THYM, UCEC, and HNSC. The result is that the expression of malignancy was revealed by the immune cells' invasion.profile of ICOS in different types of cancer. Different ways that ICOS expression is connected to immune cell infiltration account for variations in patient survival. Additionally, the TMB, MSI, MMR, and DNMT genes as well as ICOS expression are linked in many cancer types.The results of PCR showed that it is highly expressed in gastric, breast, liver and renal cell carcinoma cell lines compared with normal cells. Conclusion: This study suggests that ICOS may be a potential tumor immunotherapy target and prognostic marker. [ABSTRACT FROM AUTHOR]

Background: Establishing an appropriate prognostic model for PCa is essential for its effective treatment. Glycolysis is a vital energy-harvesting mechanism for tumors. Developing a prognostic model for PCa based on glycolysis-related genes is novel and has great potential. Methods: First, gene expression and clinical data of PCa patients were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), and glycolysis-related genes were obtained from the Molecular Signatures Database (MSigDB). Gene enrichment analysis was performed to verify that glycolysis functions were enriched in the genes we obtained, which were used in nonnegative matrix factorization (NMF) to identify clusters. The correlation between clusters and clinical features was discussed, and the differentially expressed genes (DEGs) between the two clusters were investigated. Based on the DEGs, we investigated the biological differences between clusters, including immune cell infiltration, mutation, tumor immune dysfunction and exclusion, immune function, and checkpoint genes. To establish the prognostic model, the genes were filtered based on univariable Cox regression, LASSO, and multivariable Cox regression. Kaplan--Meier analysis and receiver operating characteristic analysis validated the prognostic value of the model. A nomogram of the risk score calculated by the prognostic model and clinical characteristics was constructed to quantitatively estimate the survival probability for PCa patients in the clinical setting. Result: The genes obtained from MSigDB were enriched in glycolysis functions. Two clusters were identified by NMF analysis based on 272 glycolysis-related genes, and a prognostic model based on DEGs between the two clusters was finally established. The prognostic model consisted of LAMPS, SPRN, ATOH1, TANC1, ETV1, TDRD1, KLK14, MESP2, POSTN, CRIP2, NAT1, AKR7A3, PODXL, CARTPT, and PCDHGB2. All sample, training, and test cohorts from The Cancer Genome Atlas (TCGA) and the external validation cohort from GEO showed significant differences between the high-risk and low-risk groups. The area under the ROC curve showed great performance of this prognostic model. Conclusion: A prognostic model based on glycolysis-related genes was established, with great performance and potential significance to the clinical application. [ABSTRACT FROM AUTHOR]

Phosphatase and tensin homolog (PTEN) is one of the highly susceptible genes to breast cancer (BC); however, the role of PTEN-related RNAs in BC remains poorly understood. Understanding the effect of PTEN-related RNAs and their mechanisms may be helpful to clinicians. We screened the differentially expressed RNAs (deRNAs) related to PTEN and established the competitive endogenous RNA (ceRNA) network by integrating several databases. After that, the RNA model, prolactin receptor (PRLR)/calcium voltage-gated channel auxiliary subunit alpha2delta 1 (CACNA2D1), was obtained by KM survival analysis and logistic regression analysis. Finally, mutation, methylation, functional enrichment, and immune correlation were analyzed to explore the roles of these RNAs. Our results showed that PRLR might be harmful to BC, while CACNA2D1 might be beneficial to BC. Furthermore, the abnormal expression of PRLR in BC might result from mutation and hypomethylation, while the aberrant expression of CACNA2D1 might be ascribed to methylation. Mechanistically, PRLR might affect the prognosis of BC by inhibiting the expression of immune checkpoints, while CACNA2D1 might improve the prognosis of BC by increasing the immune cells infiltrating into BC and up-regulating the expression of immune checkpoints. The abnormal expression of PRLR and CACNA2D1 in BC is closely related to the prognosis of BC, and they may serve as targets for the treatment of BC. [ABSTRACT FROM AUTHOR]

Background: N7-Methylguanosine (m7G) and long non-coding RNAs (lncRNAs) have been widely studied in cancer and have been found to be useful for assessing tumor progression. However, the role of m7G-related lncRNAs in lung squamous cell carcinoma (LUSC) remains unclear. Thus, it is crucial to identify m7G-associated lncRNAs with definitive prognostic value. This study aimed to investigate the prognostic value, correlation with tumor mutation burden, and impact on the tumor immune microenvironment of m7G-related lncRNAs in LUSC.  METHODS: LUSC transcriptome data and clinical data were downloaded from The Cancer Genome Atlas, and an m7G-related lncRNA-mRNA co-expression network was constructed using Pearson's correlation analysis. Cox regression analyses were used to determine a risk model for m7G-associated lncRNAs with prognostic value. The risk signature was verified using the Kaplan-Meier method, receiver operating characteristic curve analysis, and principal component analysis. A nomogram based on risk scores and clinical characteristics was then developed. Gene set enrichment analysis was used for functional annotation to analyze the risk signature. The association among the risk signature, tumor mutational burden, and tumor-infiltrating immune cells was then analyzed. RT-qPCR was used to investigate the expression of 6 m7G-related lncRNAs in LUSC cells. The cytological function of SRP14-AS1 was verified by wound-healing assay and transwell assay.Results: A total of 293 m7G-related lncRNAs were identifed, 27 candidate m7G-related lncRNAs were signifcantly associated with overall survival (OS). Six of these lncRNAs (CYP4F26P, LINC02178, MIR22HG, SRP14-AS1, TMEM99, PTCSC2) were selected for establishment of the risk model. The OS of patients in the low-risk group was higher than that of patients in the high-risk group (p < 0.001). Multivariate cox regression analysis indicated that the model could be an independent prognostic factor for LUSC (HR = 1.859; 95% CI 1.452-2.380, p < 0.001). The ROC curve analysis revealed that the AUCs for OS in the 3-, and 5-year were 0.682, 0.657, respectively. GSEA analysis revealed that the risk model was closely related to immune-related pathways. Compared with normal lung epithelial cells, four m7G-related lncRNAs were higher expressed in cancer cells and two were lower expressed, among which knockdown of SRP14-AS1 promoted the proliferation and migration of LUSC cells.Conclusion: A risk model based on six m7G-related lncRNAs with prognostic value may be a promising prognostic tool in LUSC and guide individualized patient treatment. [ABSTRACT FROM AUTHOR]

• The review offers a detailed comparison of the various approaches employed to reverse T cell exhaustion in the TME, and the identification of multifaceted combination strategies for reversing T cell exhaustion is highlighted as a pivotal avenue for future clinical research endeavors. T cells suffer from long-term antigen stimulation and insufficient energy supply, leading to a decline in their effector functions, memory capabilities, and proliferative capacity, ultimately resulting in T cell exhaustion and an inability to perform normal immune functions in the tumor microenvironment. Therefore, exploring how to restore these exhausted T cells to a state with effector functions is of great significance. Exhausted T cells exhibit a spectrum of molecular alterations, such as heightened expression of inhibitory receptors, shifts in transcription factor profiles, and modifications across epigenetic, metabolic, and transcriptional landscapes. This review provides a comprehensive overview of various strategies to reverse T cell exhaustion, including immune checkpoint blockade, and explores the potential synergistic effects of combining multiple approaches to reverse T cell exhaustion. It offers new insights and methods for achieving more durable and effective reversal of T cell exhaustion. [ABSTRACT FROM AUTHOR]

[Display omitted] • This study identified RNMT characteristics in pan-cancer using multiomics data. • RNMT expression correlated with prognosis and immune infiltration in pan-cancer. • This study revealed the importance of RNMT in LUSC was superior to clinical factors based on 1287 machine learning models. • RNMT may become a biomarker due to its abnormal expression associated with the prognosis and immunity in pan-cancer. Dysregulation of RNA guanine-7 methyltransferase (RNMT) plays a crucial role in the tumor progression and immune responses. However, the detailed role of RNMT in pan-cancer is still unknown. Bulk transcriptomic data of pan-cancer were obtained from the Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), and Cancer Cell Line Encyclopedia (CCLE) databases. Single-cell transcriptomic and proteomics data of lung squamous cell carcinoma (LUSC) were analyzed in the Tumor Immune Single-cell Hub 2 (TISCH2) and Clinical Proteomic Tumor Analysis Consortium (CPTAC) databases, respectively. The correlation between RNMT expression and cancer prognosis was analyzed by Cox proportional hazards regression and Kaplan–Meier analyses. The correlation of RNMT expression with common immunoregulators, tumor mutation burden (TMB), microsatellite instability (MSI), mismatch repair (MMR), and DNA methyltransferase (DNMT) was analyzed. Additionally, the correlation between RNMT expression and immune infiltration level was evaluated. A total of 1287 machine learning combinations were used to construct prognostic models for LUSC. qRT-PCR and Western blot were used to validate the bioinformatics findings of RNMT upregulation in LUSC. RNMT was widely expressed across different cancers, with significant correlation to prognosis in cancers such as kidney chromophobe (KICH) (p = 0.0033, HR = 7.12), liver hepatocellular carcinoma (LIHC) (p = 0.01, HR = 1.41), and others. Notably, RNMT participates in the regulation of the tumor microenvironment. RNMT expression positively correlated with immune cell expression (Spearman's rank correlation, p < 0.05). Moreover, RNMT expression was strongly associated with immunoregulators, TMB, MSI, MMR, and DNMT in most cancer types. Notably, RNMT expression displayed excellent prognostic and immunological performance in LUSC. The expression of RNMT was mainly enriched in B cells of LUSC tissues. qRT–PCR and Western blot verified the high expression of RNMT in LUSC. RNMT expression widely correlated with prognosis and immune infiltration in various tumors, especially LUSC. The RNMT detection may provide a new idea for future tumor immune studies and treatment strategies. [ABSTRACT FROM AUTHOR]

C-X-C motif chemokine ligand 5 (CXCL5) is a chemokine molecule that is secreted by immune cells in attracting granulocytes. Studies showed that CXCL5 was related to the progression of papillary thyroid carcinoma (PTC) tumor cells. However, the in vivo effects of CXCL5 on PTC tumor cells and their microenvironment have not been elucidated. The present study aimed to investigate the biological effects of CXCL5 on tumor cells, microenvironment, and clinical progression of PTC. The PTC patients from The Human Cancer Genome Atlas (TCGA) – thyroid carcinoma (THCA) were retrieved. There were a total of 500 patients who met the criteria of our study. Differential expression (DEA) and pathway analyses were used to explore the biological effects of CXCL5 gene expression. In DEA, we found that CXCL5 was mostly associated with PBPP , SLC11A1 , and MRC1 (adjusted p<0.001). Samples with CXCL5 FPKM≥1 were related to a different immune profile (p<0.001). In pathway analyses, samples with higher CXCL 5 expression possessed higher activities of RAS-RAF, NF-kB, PRC2, IL2, IL5, and Wnt pathways (adjusted p<0.001). In microenvironment analysis, CXCL5 was highly correlated with the activity of macrophage (Rho=0.76; adjusted p<0.001). Clinically, high level of CXCL5 expression was an indicator of tumor stages (p<0.001), nodal metastasis (AUC=0.68), and prognosis (p=0.001). CXCL5 was a significant biomarker of PTC. CXCL5 was highly associated with tumor immunology and microenvironment. Samples with higher CXCL5 expression had more advanced disease status and worse prognosis. CXCL5 target therapy is potentially helpful in advanced PTC. [ABSTRACT FROM AUTHOR]

Background: Although mRNA vaccines have been effective against multiple cancers, their efficacy against stomach adenocarcinoma (STAD) remains undefined. 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 potential antigens in STAD for mRNA vaccine development, and further distinguish immune subtypes of STAD to construct an immune landscape for selecting suitable patients for vaccination.Methods: The gene expression and clinicopathological features of patients with gastric cancer were downloaded from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression Program (GTEx). 729 samples from GSE66229 and GSE84437 were downloaded through GEO and were used as the validation cohorts. Differential gene expression, genetic alterations and prognosis were analyzed using the R package, cBioPortal program and Kaplan-Meier. The relationship between tumor antigens and immune cells was evaluated and plotted by TIMER. ConsensusClusterPlus was used for consistency matrix construction and data clustering, and graph learning-based dimensional reduction was used to depict immune landscape. WGCNA was used to estimate the relationship between the color modules and immune subtypes.Results: Two overexpressed and mutated tumor antigens associated with poor prognosis and infiltration of antigen presenting cells were identified in STAD, including RAI14 and NREP. The immune subtypes showed distinct molecular, cellular and clinical characteristics. IS1 and IS2 exhibited immune-activated phenotypes and correlated to better survival compared to IS3, while IS3 tumors was immunologically cold. Immunogenic cell death modulators, immune checkpoints, and CA125, and CEA were also differentially expressed among the three immune subtypes. Finally, the immune landscape of STAD showed a high degree of heterogeneity between individual patients.Conclusion: RAI14 and NREP are potential antigens for developing anti-STAD mRNA vaccine, and patients with IS1 and IS3 tumors may be suitable for vaccination.

Background: TNBC, whose clinical prognosis is poorer than other subgroups of breast cancer, is a malignant tumor characterized by lack of estrogen receptors, progesterone hormone receptors, and HER2 overexpression. Due to the lack of specific targeted drugs, it is crucial to identify critical factors involved in regulating the progression of TNBC. Methods: We analyzed the expression profiles of TNBC in TCGA and the prognoses values of GLDC. Correlations of GLDC and tumor immune infiltration were also identified. CCK8 and BrdU incorporation assays were utilized to determine cell proliferation. The mRNA and protein levels were examined by using Real-time PCR and Western blot analysis. Results: In the present study, we analyzed the mRNA expression profiles of TNBC in TCGA and found that GLDC, a key enzyme in glycine cleavage system, was significantly up-regulated in TNBC tissues and higher expression of GLDC was correlated with a worse prognosis in TNBC. Moreover, the expression of GLDC was negatively correlated with macrophage and monocyte and positively correlated with activated CD4 T cell and type 2 T helper cell in TNBC. Overexpression of GLDC facilitated the proliferation of TNBC cells, whereas GLDC knockdown had the opposite effects. Additionally, miR-30e acts as a functional upstream regulator of GLDC and the inhibitory effects of miR-30e on cell proliferation were mitigated by the reintroduction of GLDC. Conclusions: These results imply that miR-30e-depressed GLDC acts as a tumor suppressive pathway in TNBC and provides potential targets for the treatment of TNBC. [ABSTRACT FROM AUTHOR]

Background: Immunotherapy using programmed cell death protein 1/ programmed death-ligand 1 (PD-1/PD-L1) inhibitors seems less effective in non-small cell lung cancer (NSCLC) patients with epithelial growth factor receptor (EGFR) mutations. Varied responses to PD-1/PD-L1 inhibitors have recently been observed in NSCLC patients harboring different types of EGFR mutations. Some EGFR-mutated NSCLC patients may benefit from PD-1/PD- L1 inhibitors. At present, PD-L1 expression, tumor mutational burden (TMB), and tumor immune microenvironment (TIME) are biomarkers for predicting the efficacy of PD-1/PD-L1 inhibitors in NSCLC patients. We retrospectively evaluated PD-L1 expression, TMB, and immune cell infiltration in NSCLC patients with EGFR mutation subtypes. Methods: PD-L1 expression, TMB, and the abundance of immune cell infiltration in NSCLC patients were evaluated in public databases and clinical samples. TMB was detected using the NGS technique, PD-L1 was detected using immunohistochemistry, and the abundance of immune cell infiltration in NSCLC samples was detected using multiple immunohistochemistry. Results: PD-L1 expression and TMB were lower in EGFR-mutated NSCLCs than in wild-type patients. Differences in the abundance of immune cell infiltration were also observed between EGFR-mutated and wild-type NSCLC. The expression of PD-L1, TMB, and abundance of immune cell infiltration were different in patients harboring different subtypes of EGFR mutations. Patients with uncommon EGFR mutations, especially the G719X mutation, showed higher TMB and expressions of PD-L1 than classical EGFR mutations. M1 macrophages were higher in uncommon EGFR mutations than classical EGFR mutations. Conclusions: The expression of PD-L1 and TMB in uncommon EGFR-mutated NSCLCs, especially the G719X mutation, were higher than those for classical EGFR-mutated NSCLCs and similar to EGFR wild-type. The abundance of immune cell infiltration in uncommon EGFR-mutated NSCLCs was similar to that in EGFR wild-type. Our findings suggest that uncommon EGFR-mutated NSCLCs may benefit from PD-1/PD-L1 inhibitors. [ABSTRACT FROM AUTHOR]

ATP citrate lyase (ACLY) is activated in various cancers, but its role in clear cell renal cell carcinoma (ccRCC) remains poorly understood. Herein, we investigated the prognostic role and potential mechanism of ACLY in ccRCC. The expression profile of ACLY in ccRCC was explored using Gene Expression Profiling Interactive Analysis 2 (GEPIA2), Gene Expression Omnibus (GEO), UALCAN and western blotting assays. The prognosis was investigated using immunohistochemistry (IHC) and Kaplan-Meier plotter assays. The relationship with immune infiltration was further evaluated using Tumor Immune Estimation Resource 2 (TIMER2) and Tumor Immune System Interactions and DrugBank (TISIDB) databases, respectively. Further biological function of ACLY in ccRCC pathogenesis was explored using in vitro experiments. ACLY level was higher in ccRCC than adjacent kidney tissues, and Kaplan-Meier survival analysis showed ACLY mRNA or protein were predictors of poor prognosis in ccRCC patients. Importantly, we reported for the first time that ACLY gene expression was significantly correlated with numerous immune cells and immune inhibitors in ccRCC. ACLY inhibition significantly impaired cell proliferation, induced cell apoptosis, attenuated cell migration, decreased lipid droplets formation, and suppressed epithelial-mesenchymal transition (EMT) of ccRCC. Moreover, these effects might be acted through mammalian target of rapamycin complex 1 (mTORC1) pathway. Collectively, ACLY was not only implicated in ccRCC tumorigenesis and progression, but also potentially interacted with immune infiltration and mTORC1 pathway. Our findings may provide a novel therapeutic strategy by targeting ACLY for ccRCC treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Chengwen Zhao,1,&ast; Yonghui Liu,1,&ast; Shaoqing Ju,1,2 Xudong Wang1,2 1Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, Jiangsu, People’s Republic of China; 2Department of Public Health, Nantong University, Nantong, Jiangsu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xudong WangDepartment of Laboratory Medicine, Affiliated Hospital of Nantong University, 20 Xisi Road, Nantong, Jiangsu, 226006, People’s Republic of ChinaTel +86 13951318000Email wangxudong88@hotmail.comBackground: Fat mass and obesity-associated protein (FTO) is a critical N6-methyladenosine (m6A) demethylase that participates in tumorigenesis and is associated with the prognosis of patients in some cancers. However, the key roles of FTO in pan-cancer are still largely obscure.Methods: FTO expression levels in pan-cancer were estimated via the Genotype-Tissue Expression (GTEx), Cancer Cell Line Encyclopedia (CCLE), and The Cancer Genome Atlas (TCGA) databases. Univariate survival analysis was used to estimate the effects of FTO on prognosis. In addition, we used the Tumor Immune Evaluation Resource (TIMER) to assess the immune cell infiltration of FTO gene across cancers. The association of FTO expression with immune checkpoint genes expression, DNA mismatch repair (MMR) gene mutation, DNA methyltransferases, microsatellite instability (MSI), and tumor mutational burden (TMB) was investigated using Spearman’s correlation analysis. Moreover, Gene Set Enrichment Analysis (GSEA) was utilized to identify critical pathways in cancers. The STRING website was used to reveal the protein–protein interaction (PPI) network of FTO.Results: FTO was aberrantly expressed across cancers and survival analysis demonstrated that its expression was associated with clinical prognosis of many cancer patients. Specifically, FTO expression was significantly associated with immune infiltrating cells in colon adenocarcinoma, kidney renal clear cell carcinoma, and liver hepatocellular carcinoma. In addition, FTO expression was significantly associated with immune checkpoint genes expression, MMR, DNA methyltransferases levels, TMB, and MSI in multiple cancers. Moreover, the GSEA unveiled that FTO was involved in the regulation of tumors and immune-related signaling pathways. In addition, several m6A related genes were implicated in the PPI network of FTO.Conclusion: FTO was related to patients’ prognosis and tumor immune infiltrates in various cancers, and may serve as a novel and potential prognostic and immune biomarker in human pan-cancer.Keywords: FTO, biomarker, prognosis, tumor immune, pan-cancer

Pancreatic cancer (PC) is the most lethal malignancy worldwide due to its delayed diagnosis and limited treatment options. Despite great progress in clinical trials of immunotherapies for various cancers, their effectiveness in PC is very low, indicating that immune evasion is still a major obstacle to immunotherapy in PC. However, the mechanism of immune escape in PC is not fully understood, which substantially restricts the development of immunotherapy. As an important component of intercellular communication networks, extracellular vesicles (EVs) have attracted increasing attention in relation to immune escape. This review aims to provide a better understanding of the roles of EVs in tumor immune escape and the potential to expand their application in cancer immunotherapy. The relationship between PC and the tumor immune microenvironment is briefly introduced. Then, the mechanism by which EVs are involved in immune regulation is summarized, and the latest progress in determining the role of EVs in regulating PC immune escape is highlighted.

BackgroundRecent evidence suggests that enhancer RNAs (eRNAs) play key roles in cancers. Identification of immune-related eRNAs (ireRNAs) in melanoma can provide novel insights into the mechanisms underlying its genesis and progression, along with potential therapeutic targets.AimTo establish an ireRNA-related prognostic signature for melanoma and identify potential drug candidates.MethodsThe ireRNAs associated with the overall survival (OS-ireRNAs) of melanoma patients were screened using data from The Cancer Genome Atlas (TCGA) via WGCNA and univariate Cox analysis. A prognostic signature based on these OS-ireRNAs was then constructed by performing the least absolute shrinkage and selection operator (LASSO) Cox regression analysis. The immune landscape associated with the prognostic model was evaluated by the ESTIMATE algorithm and CIBERSORT method. Finally, the potential drug candidates for melanoma were screened through the cMap database.ResultsA total of 24 OS-ireRNAs were obtained, of which 7 ireRNAs were used to construct a prognostic signature. The ireRNAs-related signature performed well in predicting the overall survival (OS) of melanoma patients. The risk score of the established signature was further verified as an independent risk factor, and was associated with the unique tumor microenvironment in melanoma. We also identified several potential anti-cancer drugs for melanoma, of which corticosterone ranked first.ConclusionsThe ireRNA-related signature is an effective prognostic predictor and provides reliable information to better understand the mechanism of ireRNAs in the progression of melanoma.

Lung adenocarcinoma is increasingly harmful to society and individuals as cancer with an inferior prognosis and insensitive to chemotherapy. Previous studies have demonstrated that oxidative stress and lncRNAs play a vital role in many biological processes. Therefore, we explored the role of lncRNAs associated with oxidative stress in the prognosis and survival of LUAD patients. We examined the expression profiles of lncRNAs and oxidative stress genes in this study. A prognosis prediction model and a nomogram were built based on oxidative stress-related lncRNAs. Functional and drug sensitivity analyses were also performed depending on oxidative stress-related lncRNA signature. Moreover, we investigated the relationship between immune response and immunotherapy. The results showed that a risk scoring model based on 16 critical oxidative stress lncRNAs was able to distinguish the clinical status of LUAD and better predict the prognosis and survival. Additionally, the model demonstrated a close correlation with the tumor immune system, and these key lncRNAs also revealed the relationship between LUAD and chemotherapeutic drug sensitivity. Our work aims to provide new perspectives and new ideas for the treatment and management of LUAD. [ABSTRACT FROM AUTHOR]

Ovarian cancer (OC) is a highly malignant gynecologic tumor with few treatments available and poor prognosis with the currently available diagnostic markers and interventions. More effective methods for diagnosis and treatment are urgently needed. Although the current evidence implicates ferroptosis in the development and therapeutic responses of various types of tumors, it is unclear to what extent ferroptosis affects OC. To explore the potential of ferroptosis-related genes as biomarkers and molecular targets for OC diagnosis and intervention, this study collected several datasets from The Cancer Genome Atlas-OC (TCGA-OC), analyzed and identified the coexpression profiles of 60 ferroptosis-related genes and two subtypes of OC with respect to ferroptosis and further examined and analyzed the differentially expressed genes between the two subtypes. The results indicated that the expression levels of ferroptosis genes were significantly correlated with prognosis in patients with OC. Single-factor Cox and LASSO analysis identified eight lncRNAs from the screened ferroptosis-related genes, including lncRNAs RP11-443B7.3, RP5-1028K7.2, TRAM2-AS1, AC073283.4, RP11-486G15.2, RP11-95H3.1, RP11-958F21.1, and AC006129.1. A risk scoring model was constructed from the ferroptosis-related lncRNAs and showed good performance in the evaluation of OC patient prognosis. The high- and low-risk groups based on tumor scores presented obvious differences in clinical characteristics, tumor mutation burden, and tumor immune cell infiltration, indicating that the risk score has a good ability to predict the benefit of immunotherapy and may provide data to support the implementation of precise immunotherapy for OC. Although in vivo tests and research are needed in the future, our bioinformatics analysis powerfully supported the effectiveness of the risk signature of ferroptosis-related lncRNAs for prognosis prediction in OC. The findings suggest that these eight identified lncRNAs have great potential for development as diagnostic markers and intervention targets for OC and that patients with high ferroptosis-related lncRNA expression will receive greater benefits from conventional chemotherapy or treatment with ferroptosis inducers. [ABSTRACT FROM AUTHOR]

Objective: To investigate the role of CXCL5 in tumor immune of lung cancer and to explore the potential molecular mechanisms. Methods: A total of 62 cases of patients with lung cancer admitted in the First Affiliated Hospital of Henan University from May 2018 to December 2019 were recruited as study object. Another 20 cases of patients with pulmonary infectious diseases and 20 cases of healthy control were selected as control. Enzyme-linked immunosorbent assay (ELISA) was used to determine serum levels of CXCL5 in patients with lung cancer, pulmonary infectious diseases and healthy control. Immunohistochemical staining (IHC) was used to detect the expressions of CXCL5 and PD-1/PD-L1 in tumor and paracarcinoma tissues of patients with lung cancer. Pearson correlation analysis was used to evaluate the correlation between CXCL5 and PD-1 in tumor and paracarcinoma tissues of patients with lung cancer. Lewis cells either expressing CXCL5 or vector plasmids were used to establish C57BL/6J mice model of lung cancer, and all mice were then divided into vehicle and PD-1 antibody treatment groups, 10 mice for each group. The mice survival and tumor growth curves were recorded. IHC was used to evaluate the expressions of CXCL5, PD-1 as well as the proportions of CD8(+) T and Treg cells in xenograft tumor tissues. Results: In patients with lung cancer, the serum level of CXCL5 [(351.7±51.5) ng/L] was significant higher than that in patients with pulmonary infectious diseases and healthy control [(124.7±23.4) ng/L, P<0.001]. The expression levels of CXCL5 (0.136±0.034), CXCR2 (0.255±0.050), PD-1 (0.054±0.012) and PD-L1 (0.350±0.084) in tumor were significant higher than those in paracarcinoma normal tissues [(0.074±0.022), (0.112±0.023), (0.041±0.007) and (0.270±0.043) respectively, P<0.001]. CXCL5 was significant positively correlated with PD-1 in tumor tissues of lung cancer (r=0.643, P<0.001), but not correlated with PD-1 in paracarcinoma tissues(r=0.088, P=0.496). The vector control group, CXCL5 overexpression group, vector control + anti-PD-1 antibody treatment group and CXCL5 overexpression + anti-PD-1 antibody treatment group all successfully formed tumors in mice, while CXCL5 overexpression increased the tumor growth significantly (P<0.01), which was abrogated by the treatment of anti-PD-1 antibody. CXCL5 overexpression decreased the mice survival time significantly (P<0.01), this effect was also abrogated by the treatment of anti-PD-1 antibody. The proportion of CD8(+) T cells in CXCL5 overexpression group [(10.40±2.00)%] was significant lower than that in vector control group [(21.20±3.30)%, P=0.002]. The proportion of CD4(+) Foxp3(+) Treg cells in CXCL5 overexpression group [(38.40±3.70)%] was significant higher than that in vector control group [(23.30±2.25)%, P<0.001]. After the treatment of anti-PD-1 antibody, no significant difference were observed for the proportion of CD8(+) T cells [(34.10±5.00)% and (33.40±4.00)% respectively] and Treg cells [(14.70±3.50)% and (14.50±3.30)% respectively] in xenograft tumor tissues between CXCL5 overexpression+ anti-PD-1 antibody treatment group and vector control + anti-PD-1 antibody treatment group (P>0.05). Conclusion: The expressions of CXCL5 and PD-1/PD-L1 are all increased significantly in the tumor tissues of patients with lung cancer, CXCL5 may inhibit tumor immune of lung cancer via modulating PD-1/PD-L1 signaling. [ABSTRACT FROM AUTHOR]

Prostate cancer (PCa) currently ranks second in male tumor mortality. Targeting immune checkpoint in tumor as immunotherapy is a new direction for tumor treatment. However, targeting PD-1/PD-L1 and CTLA4 to treat PCa has poor immunotherapeutic efficacy because PCa is known as a cold tumor. Understanding the mechanism of immunosuppression in PCa can promote the use of immunotherapy to treat PCa. ELAVL1 is highly expressed in many tumors, participates in almost all tumor biological activities and is an oncogene. ELAVL1 is also involved in the development and differentiation of T and B lymphocytes. However, the relationship between ELAVL1 and tumor immunity has not yet been reported. In recent years, ELAVL1 has been shown to regulate downstream targets in an m6A -dependent manner. PD-L1 has been shown to have m6A sites in multiple tumors that are regulated by m6A. In this study, ELAVL1 was highly expressed in PCa, and PCa with high ELAVL1 expression is immunosuppressive. Knocking down ELAVL1 reduced PD-L1 expression in PCa. Moreover, PD-L1 was shown to have an m6A site, and its m6A level was upregulated in PCa. ELAVL1 interacts with PD-L1 mRNA and promotes PD-L1 RNA stability via m6A, ultimately inhibiting the infiltration of CD4-positive T cells. In addition, androgen receptor (AR) was shown to be regulated with ELAVL1, and knocking down AR could also affect the expression of PD-L1. Therefore, ELAVL1 can directly or indirectly regulate the expression of PD-L1, thereby affecting the infiltration of CD4-positive T cells in PCa and ultimately leading to immune suppression. [ABSTRACT FROM AUTHOR]

Lung adenocarcinoma is increasingly harmful to society and individuals as cancer with an inferior prognosis and insensitive to chemotherapy. Previous studies have demonstrated that oxidative stress and lncRNAs play a vital role in many biological processes. Therefore, we explored the role of lncRNAs associated with oxidative stress in the prognosis and survival of LUAD patients. We examined the expression profiles of lncRNAs and oxidative stress genes in this study. A prognosis prediction model and a nomogram were built based on oxidative stress-related lncRNAs. Functional and drug sensitivity analyses were also performed depending on oxidative stress-related lncRNA signature. Moreover, we investigated the relationship between immune response and immunotherapy. The results showed that a risk scoring model based on 16 critical oxidative stress lncRNAs was able to distinguish the clinical status of LUAD and better predict the prognosis and survival. Additionally, the model demonstrated a close correlation with the tumor immune system, and these key lncRNAs also revealed the relationship between LUAD and chemotherapeutic drug sensitivity. Our work aims to provide new perspectives and new ideas for the treatment and management of LUAD.

Ovarian cancer (OC) is a highly malignant gynecologic tumor with few treatments available and poor prognosis with the currently available diagnostic markers and interventions. More effective methods for diagnosis and treatment are urgently needed. Although the current evidence implicates ferroptosis in the development and therapeutic responses of various types of tumors, it is unclear to what extent ferroptosis affects OC. To explore the potential of ferroptosis-related genes as biomarkers and molecular targets for OC diagnosis and intervention, this study collected several datasets from The Cancer Genome Atlas-OC (TCGA-OC), analyzed and identified the coexpression profiles of 60 ferroptosis-related genes and two subtypes of OC with respect to ferroptosis and further examined and analyzed the differentially expressed genes between the two subtypes. The results indicated that the expression levels of ferroptosis genes were significantly correlated with prognosis in patients with OC. Single-factor Cox and LASSO analysis identified eight lncRNAs from the screened ferroptosis-related genes, including lncRNAs RP11-443B7.3, RP5-1028K7.2, TRAM2-AS1, AC073283.4, RP11-486G15.2, RP11-95H3.1, RP11-958F21.1, and AC006129.1. A risk scoring model was constructed from the ferroptosis-related lncRNAs and showed good performance in the evaluation of OC patient prognosis. The high- and low-risk groups based on tumor scores presented obvious differences in clinical characteristics, tumor mutation burden, and tumor immune cell infiltration, indicating that the risk score has a good ability to predict the benefit of immunotherapy and may provide data to support the implementation of precise immunotherapy for OC. Although in vivo tests and research are needed in the future, our bioinformatics analysis powerfully supported the effectiveness of the risk signature of ferroptosis-related lncRNAs for prognosis prediction in OC. The findings suggest that these eight identified lncRNAs have great potential for development as diagnostic markers and intervention targets for OC and that patients with high ferroptosis-related lncRNA expression will receive greater benefits from conventional chemotherapy or treatment with ferroptosis inducers.

Pancreatic cancer (PACA), which is characterized by an immunosuppressive nature, remains one of the deadliest malignancies worldwide. Aberrant DNA methylation (DNAm) reportedly influences tumor immune microenvironment. Here, we evaluated the role of DNA methylation driven genes (MDGs) in PACA through integrative analyses of epigenomic, transcriptomic, genomic and clinicopathological data obtained from TCGA, ICGC, ArrayExpress and GEO databases. Thereafter, we established a four-MDG signature, comprising GPRC5A, SOWAHC, S100A14, and ARNTL2. High signature risk-scores were associated with poor histologic grades and late TNM stages. Survival analyses showed the signature had a significant predictive effect on OS. WGCNA revealed that the signature may be associated with immune system, while high risk-scores might reflect immune dysregulation. Furthermore, GSEA and GSVA revealed significant enrichment of p53 pathway and mismatch repair pathways in high risk-score subgroups. Immune infiltration analysis showed that CD8+ T cells were more abundant in low score subgroups, while M0 macrophages exhibited an opposite trend. Moreover, negative regulatory genes of cancer-immunity cycle (CIC) illustrated that immunosuppressors TGFB1, VEGFA, and CD274 (PDL1) were all positively correlated with risk-scores. Furthermore, the four signature genes were negatively correlated with CD8+ lymphocytes, but positively associated with myeloid derived suppressor cells (MDSC). Conversely, specimens with high risk-scores exhibited heavier tumor mutation burdens (TMB) and might show better responses to some chemotherapy and targeted drugs, which would benefit stratification of PACA patients. On the other hand, we investigated the corresponding proteins of the four MDGs using paraffin-embedded PACA samples collected from patients who underwent radical surgery in our center and found that all these four proteins were elevated in cancerous tissues and might serve as prognostic markers for PACA patients, high expression levels indicated poor prognosis. In conclusion, we successfully established a four-MDG-based prognostic signature for PACA patients. We envisage that this signature will help in evaluation of intratumoral immune texture and enable identification of novel stratification biomarkers for precision therapies. [ABSTRACT FROM AUTHOR]

Background: Recent studies have confirmed that AT-rich interactive domain-containing protein 1A (ARID1A) plays a critical role in tumorigenesis, but its role in gallbladder cancer (GBC) remains unclear. Methods: In total, 224 patients from Zhongshan Hospital were recruited for this retrospective study. The clinicopathological and baseline characteristics of the patients were collected. Bioinformatics analysis was performed to reveal variations in genes and signaling pathways, and ARID1A and PD-L1 expression and the number of PD1+ tumor-infiltrating lymphocytes (TILs) were measured by immunohistochemical staining. Results: ARID1A expression was negatively correlated with overall survival in patients with GBC, and multivariate analysis identified ARID1A as an independent prognostic factor for overall survival. A heatmap and gene set enrichment analysis suggested that cytotoxic T lymphocyte signatures and immune-related signaling pathways were downregulated in ARID1A low tumors. Subsequent immunohistochemical staining confirmed that ARID1A expression was negatively correlated with PD-L1 expression and PD1+ TILs in the tumor microenvironment. The Kaplan–Meier analysis suggested that high ARID1A expression combined with low PD-L1 expression or low PD1+ TIL counts is associated with the best prognosis in patients with GBC. Conclusion: ARID1A inactivation can lead to a worse prognosis in patients with GBC, potentially by mediating immune evasion through the PD1/PD-L1 pathway. [ABSTRACT FROM AUTHOR]

BackgroundRecent studies have confirmed that AT-rich interactive domain-containing protein 1A (ARID1A) plays a critical role in tumorigenesis, but its role in gallbladder cancer (GBC) remains unclear.MethodsIn total, 224 patients from Zhongshan Hospital were recruited for this retrospective study. The clinicopathological and baseline characteristics of the patients were collected. Bioinformatics analysis was performed to reveal variations in genes and signaling pathways, and ARID1A and PD-L1 expression and the number of PD1+ tumor-infiltrating lymphocytes (TILs) were measured by immunohistochemical staining.ResultsARID1A expression was negatively correlated with overall survival in patients with GBC, and multivariate analysis identified ARID1A as an independent prognostic factor for overall survival. A heatmap and gene set enrichment analysis suggested that cytotoxic T lymphocyte signatures and immune-related signaling pathways were downregulated in ARID1A low tumors. Subsequent immunohistochemical staining confirmed that ARID1A expression was negatively correlated with PD-L1 expression and PD1+ TILs in the tumor microenvironment. The Kaplan–Meier analysis suggested that high ARID1A expression combined with low PD-L1 expression or low PD1+ TIL counts is associated with the best prognosis in patients with GBC.ConclusionARID1A inactivation can lead to a worse prognosis in patients with GBC, potentially by mediating immune evasion through the PD1/PD-L1 pathway.

Pancreatic cancer (PACA), which is characterized by an immunosuppressive nature, remains one of the deadliest malignancies worldwide. Aberrant DNA methylation (DNAm) reportedly influences tumor immune microenvironment. Here, we evaluated the role of DNA methylation driven genes (MDGs) in PACA through integrative analyses of epigenomic, transcriptomic, genomic and clinicopathological data obtained from TCGA, ICGC, ArrayExpress and GEO databases. Thereafter, we established a four-MDG signature, comprising GPRC5A, SOWAHC, S100A14, and ARNTL2. High signature risk-scores were associated with poor histologic grades and late TNM stages. Survival analyses showed the signature had a significant predictive effect on OS. WGCNA revealed that the signature may be associated with immune system, while high risk-scores might reflect immune dysregulation. Furthermore, GSEA and GSVA revealed significant enrichment of p53 pathway and mismatch repair pathways in high risk-score subgroups. Immune infiltration analysis showed that CD8+ T cells were more abundant in low score subgroups, while M0 macrophages exhibited an opposite trend. Moreover, negative regulatory genes of cancer-immunity cycle (CIC) illustrated that immunosuppressors TGFB1, VEGFA, and CD274 (PDL1) were all positively correlated with risk-scores. Furthermore, the four signature genes were negatively correlated with CD8+ lymphocytes, but positively associated with myeloid derived suppressor cells (MDSC). Conversely, specimens with high risk-scores exhibited heavier tumor mutation burdens (TMB) and might show better responses to some chemotherapy and targeted drugs, which would benefit stratification of PACA patients. On the other hand, we investigated the corresponding proteins of the four MDGs using paraffin-embedded PACA samples collected from patients who underwent radical surgery in our center and found that all these four proteins were elevated in cancerous tissues and might serve as prognostic markers for PACA patients, high expression levels indicated poor prognosis. In conclusion, we successfully established a four-MDG-based prognostic signature for PACA patients. We envisage that this signature will help in evaluation of intratumoral immune texture and enable identification of novel stratification biomarkers for precision therapies.

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