Multi-dataset identification of innovative feature genes and molecular mechanisms in keratoconus.

This study aimed to identify feature genes and explore the molecular mechanisms of keratoconus (KC). We downloaded data files from NCBI GEO public database. The Limma package was used for differential expression analysis of gene profiles. Lasso regression was used to identify the feature genes. The CIBERSORT algorithm was used to infer the proportion of immune-infiltrating cells and analyse the correlation between gene expression levels and immune cells. Related transcription factors and miRNAs of key genes were predicted using the Cistrome DB and Mircode databases. Analysis of expression differences in disease genes was based on the GeneCards database. The CMap was used to analyse targeted therapeutic drugs. IHC was performed to verify the expression levels of ATOH7 and MYRF in corneas. Exactly 593 upregulated and 473 downregulated genes were identified. Lasso regression analysis identified ATOH7, DBNDD1, RNF217-AS1, ARL11, MYRF and SNORA74B as feature genes for KC. All key genes were correlated with immune infiltration and the levels of activated memory CD4+ T cells and plasma cells were significantly increased. miRNA, IRF and STAT families were correlated to feature genes. The expression levels of key genes were significantly correlated to KC-related genes. Entinostat, ochratoxin-a, diphencyprone and GSK-3-inhibitor-II were predicted as potential KC medications. The expression of MYRF was significantly higher in the KC samples, contrary to the expression of ATOH7. KC is related to both immune infiltration and genetic factors. MYRF and ATOH7 were newly identified and verified feature genes of KC.

A correlation study of adhesion G protein-coupled receptors as potential therapeutic targets for breast cancer.

BACKGROUND: Adhesion G protein-coupled receptors (aGPCRs), a distinctive subset of the G protein-coupled receptor (GPCR) superfamily, play crucial roles in various physiological and pathological processes, with implications in tumor development. Despite the global prevalence of breast cancer (BRCA), specific aGPCRs as potential drug targets or biomarkers remain underexplored. METHODS: UALCAN, GEPIA, Kaplan-Meier Plotter, MethSurv, cBiopportal, String, GeneMANIA, DAVID, Timer, Metascape, and qPCR were applied in this work. RESULTS: Our analysis revealed significantly increased transcriptional levels of ADGRB2, ADGRC1, ADGRC2, ADGRC3, ADGRE1, ADGRF2, ADGRF4, and ADGRL1 in BRCA primary tumors. Further analysis indicated a significant correlation between the expressions of certain aGPCRs and the pathological stage of BRCA. High expression of ADGRA1, ADGRF2, ADGRF4, ADGRG1, ADGRG2, ADGRG4, ADGRG6, and ADGRG7 was significantly correlated with poor overall survival (OS) in BRCA patients. Additionally, high expression of ADGRF2 and ADGRF4 indicated inferior recurrence-free survival (RFS) in BRCA patients. The RT-qPCR experiments also confirmed that the mRNA levels of ADGRF2 and ADGRF4 were higher in BRCA cells and tissues. Functional analysis highlighted the diverse roles of aGPCRs, encompassing GPCR signaling and metabolic energy reserves. Moreover, aGPCRs may exert influence or actively participate in the development of BRCA through their impact on immune status. CONCLUSION: aGPCRs, particularly ADGRF2 and ADGRF4, hold promise as immunotherapeutic targets and prognostic biomarkers in BRCA.

Spleen tyrosine kinase inhibitor R406 has both antiviral and anti-inflammatory effects on severe influenza A infection.

Death due to severe influenza is usually a fatal complication of a dysregulated immune response more than the acute virulence of an infectious agent. Although spleen tyrosine kinase (SYK) as a critical immune signaling molecule and therapeutic target plays roles in airway inflammation and acute lung injury, the role of SYK in influenza virus infection is not clear. Here, we investigated the antiviral and anti-inflammatory effects of SYK inhibitor R406 on influenza infection through a coculture model of human alveolar epithelial (A549) and macrophage (THP-1) cell lines and mouse model. The results showed that R406 treatment increased the viability of A549 and decreased the pathogenicity and mortality of lethal influenza virus in mice with influenza A infection, decreased levels of intracellular signaling molecules under the condition of inflammation during influenza virus infection. Combination therapy with oseltamivir further ameliorated histopathological damage in the lungs of mice and further delayed the initial time to death compared with R406 treatment alone. This study demonstrated that phosphorylation of SYK is involved in the pathogenesis of influenza, and R406 has antiviral and anti-inflammatory effects on the treatment of the disease, which may be realized through multiple pathways, including the already reported SYK/STAT/IFNs-mediated antiviral pathway, as well as TNF-α/SYK- and SYK/Akt-based immunomodulation pathway.

Identification of the MMP family as therapeutic targets and prognostic biomarkers in the microenvironment of head and neck squamous cell carcinoma.

BACKGROUND: Head and Neck Squamous Cell Carcinoma is a malignant tumor with high morbidity and mortality. The MMP family plays an important role in tumor invasion and metastasis. However, the mechanistic value of the MMP family as a therapeutic target and prognostic biomarker in HNSC has not been fully elucidated. METHODS: Oncomine, UALCAN, GEPIA, cBioportal, GeneMANIA, STRING, DAVID6.8, TRRUST, TIMER and Linkedomics were used for analysis. RESULTS: The mRNA expression levels of MMP1, MMP3, ILF3, MMP7, MMP9, MMP10, MMP11, MMP12, MMP13 and MMP16 were higher in HNSC than those in normal tissues, while the mRNA expression level of MMP15 was reduced. The relative expression levels of MMP1 and MMP14 were the highest in HNSC tissues. A significant correlation was found between the expression of MMP3, MMP11, MMP25 and the pathological stage of HNSC patients. There was no significant associations between all the MMP family members expression levels and DFS. Increased mRNA levels of MMP1, MMP8 and MMP25 were significantly associated with OS. In addition, we investigated the genetic changes of the MMP family in HNSC and found that all the MMP family members had genetic changes, most of which were amplification and depth loss. In the analysis of neighbor gene network and protein interaction, we found that the MMP family interacted with 25 neighboring genes, except for ILF3, MMP19, MMP20, MMP21, MMP23B, MMP27 and MMP28, other MMP proteins interacted with each other. Functional enrichment analysis showed that the MMP family could be present in the extracellular matrix, regulate peptidase activity, and participate in the catabolism of collagen. Meanwhile, we identified the transcription factor targets and kinase targets of the MMP family and found that ATM and ATR were the two most common kinase targets in the MMP family. We also found a significant correlation between the MMP family expression and immune cell infiltration. Cox proportional risk model analysis showed that macrophages, MMP14, MMP16, and MMP19 were significantly associated with clinical outcomes in HNSC patients. CONCLUSION: The MMP family might serve as therapeutic target and prognostic biomarker in HNSC.

Strategies to Overcome Resistance to Immune-Based Therapies in Osteosarcoma.

Improving the prognosis and cure rate of HGOSs (high-grade osteosarcomas) is an absolute need. Immune-based treatment approaches have been increasingly taken into consideration, in particular for metastatic, relapsed and refractory HGOS patients, to ameliorate the clinical results currently achieved. This review is intended to give an overview on the immunotherapeutic treatments targeting, counteracting or exploiting the different immune cell compartments that are present in the HGOS tumor microenvironment. The principle at the basis of these strategies and the possible mechanisms that HGOS cells may use to escape these treatments are presented and discussed. Finally, a list of the currently ongoing immune-based trials in HGOS is provided, together with the results that have been obtained in recently completed clinical studies. The different strategies that are presently under investigation, which are generally aimed at abrogating the immune evasion of HGOS cells, will hopefully help to indicate new treatment protocols, leading to an improvement in the prognosis of patients with this tumor.

Opa-Interacting Protein 5 Expression in Human Glioma Tissues Is Essential to the Biological Function of U251 Human Malignant Glioma Cells.

Opa-interacting protein 5 (OIP5) is a member of the cancer-testis antigen (CTA) family that elicits a spontaneous antitumor immune response. The failure of current immunotherapies for glioma has prompted the search for novel biomarkers that may be utilized as therapeutic targets. This study aimed to investigate whether OIP5 serves as a target for malignant glioma immunotherapy. Glioma specimens from 53 adult patients were evaluated for OIP5 expression by immunohistochemical (IHC) staining, and the correlation of OIP5 expression with World Health Organization (WHO) tumor grade was analyzed. Endogenous expression of OIP5 in glioma cell lines was determined via real-time polymerase chain reaction (RT-PCR). Using lentiviral siOIP5, the effect of OIP5 gene knockdown on proliferation, cell cycle, and apoptosis in U251 glioma cells was studied. The results show that OIP5 is overexpressed in glioma tissues and is correlated with WHO tumor grade (P < 0.001). However, OIP5 protein expression is barely detectable in normal adult brain tissues. MTT assays and analysis using the Celigo Imaging Cytometry System reveal that the silencing of OIP5 inhibits U251 cell growth. Cell cycle assays and Annexin V staining show that OIP5 silencing disrupts the balance of the cell cycle and increases U251 cell death. These results indicate that OIP5 is upregulated in malignant glioma specimens but barely detected in normal brain tissues. OIP5 knockdown inhibits the biological function of glioma cells, reinforcing that OIP5 may serve as an immunotherapeutic target for malignant glioma.

Design, Synthesis and Biological Evaluation of Phenyl Urea Derivatives as IDO1 Inhibitors.

Indoleamine 2,3-dioxygenase 1 (IDO1) is a heme-containing intracellular enzyme that catalyzes the first and rate-determining step of tryptophan metabolism and is an important immunotherapeutic target for the treatment of cancer. In this study, we designed and synthesized a new series of compounds as potential IDO1 inhibitors. These compounds were then evaluated for inhibitory activity against IDO1 and tryptophan 2,3-dioxygenase (TDO). Among them, the three phenyl urea derivatives i12, i23, i24 as showed potent IDO1 inhibition, with IC50 values of 0.1-0.6 µM and no compound exhibited TDO inhibitory activity. Using molecular docking, we predicted the binding mode of compound i12 within IDO1. Compound i12 was further investigated by determining its in vivo pharmacokinetic profile and anti-tumor efficacy. The pharmacokinetic study revealed that compound i12 had satisfactory properties in mice, with moderate plasma clearance (22.45 mL/min/kg), acceptable half-life (11.2 h) and high oral bioavailability (87.4%). Compound i12 orally administered at 15 mg/kg daily showed tumor growth inhibition (TGI) of 40.5% in a B16F10 subcutaneous xenograft model and 30 mg/kg daily showed TGI of 34.3% in a PAN02 subcutaneous xenograft model. In addition, the body weight of i12-treated mice showed no obvious reduction compared with the control group. Overall, compound i12 is a potent lead compound for developing IDO1 inhibitors and anti-tumor agents.

SRRM2 may be a potential biomarker and immunotherapy target for multiple myeloma: a real-world study based on flow cytometry detection.

Serine/arginine repetitive matrix 2 (SRRM2) has been implicated in tumorigenesis, cancer development, and drug resistance through aberrant splicing; however, its correlation with multiple myeloma (MM) has not been reported. We investigated the potential of SRRM2 as a biomarker and immunotherapeutic target in MM by examining its expression in MM cells using flow cytometry. Our study included 95 patients with plasma cell disease, including 80 MM cases, and we detected SRRM2 expression on plasma cells and normal blood cells to analyze its relationship with clinical profiles. We found widespread positive expression of SRRM2 on plasma cells with little expression on normal blood cells, and its expression on abnormal plasma cells was higher than that on normal plasma cells. Comparative analysis with clinical data suggests that SRRM2 expression on plasma cells correlates with MM treatment response. MM patients with high SRRM2 expression had higher levels of serum ß2-mg and LDH, ISS staging, and plasma cell infiltration, as well as high-risk mSMART 3.0 stratification and cytogenetic abnormalities, particularly 1q21 amplification. In patients with previous MM, high SRRM2 expression on plasma cells was associated with higher plasma cell infiltration, high-risk mSMART 3.0 risk stratification, cytogenetic abnormalities, more relapses, and fewer autologous stem cell transplant treatments. In summary, SRRM2 may serve as a novel biomarker and immunotherapeutic target for MM. Its expression level on plasma cells can help in risk stratification of MM and monitoring of treatment response.

Pan-Cancer Bioinformatics Indicates ZNF207 is a Promising Prognostic Biomarker and Immunotherapeutic Target.

In the era of personalized cancer treatment, understanding the complexities of tumor biology and immune modulation is paramount. This comprehensive analysis delves into the multifaceted role of Zinc Finger Protein 207 (ZNF207) in pan-cancer, shedding light on its involvement in tumorigenesis, immune evasion, and therapeutic implications. Through integrated genomic and clinical data analysis, we reveal consistent upregulation of ZNF207 across diverse cancer types, highlighting its potential as a prognostic marker and therapeutic target, particularly for liver cancers. Notably, ZNF207 demonstrates intricate associations with clinical-pathological features, immune subtypes, and molecular pathways, indicating its pervasive influence in cancer biology. Furthermore, our study uncovers ZNF207's involvement in immune escape mechanisms, suggesting its potential as a modulator of immune responses within the tumor microenvironment. These findings underscore the significance of ZNF207 in shaping cancer progression and immune landscape, presenting promising avenues for targeted therapy and immunomodulation. Recognizing ZNF207's multifaceted contributions to cancer progression and immune evasion suggests its central role in understanding tumor immunology, beyond mere therapeutic targeting. Nevertheless, further mechanistic studies are imperative to elucidate ZNF207's precise molecular mechanisms and therapeutic implications in cancer treatment. This study primarily utilized various bioinformatics tools such as TIMER 2.0, cProSite, UALCAN, SangerBox, GEPIA2, TISIDB and TIDE to analyze the expression of ZNF207 in multiple cancer samples from the TCGA database.

Pan-cancer analysis revealing the multidimensional expression and prognostic and immunologic roles of TGFB1 in cancer.

OBJECTIVE: This study aimed to perform an integrated pan-cancer analysis to characterize the expression patterns, prognostic value, genetic alterations, and immunologic roles of transforming growth factor beta 1 (TGFB1) across diverse human cancer types. METHODS: Bioinformatics analyses were conducted using multiple public databases including The Cancer Genome Atlas, Genotype-Tissue Expression, Clinical Proteomic Tumor Analysis Consortium, TIMER2, GEPIA2, cBioPortal, StringDB, and others. Differential expression, survival, immune correlation, and protein interaction network analyses were performed. RESULTS: TGFB1 was overexpressed in several tumor types compared with that in normal tissues. High TGFB1 expression was associated with an advanced stage and poorer prognosis in certain cancers. TGFB1 mutations occurred in 1.3% of 10,967 cases surveyed. TGFB1 expression correlated with tumor-infiltrating immune cells and immunotherapy-related genes. CONCLUSIONS: This comprehensive multi-omics analysis revealed the complex expression and prognostic landscape of TGFB1 across cancers. TGFB1 is emerging as a potential immunotherapeutic target in certain contexts. Further research should elucidate its multifaceted tumor-promoting and tumor-suppressive mechanisms. Our pan-cancer analysis provides new insights into TGFB1 as a prognostic biomarker and immunotherapeutic target in human cancers, and our findings may guide future preclinical and clinical investigations of TGFB1-directed therapies.

Indoleamine 2,3-Dioxygenase: A Novel Immunotherapeutic Target for Osteosarcoma.

Introduction: Tumour-emitted molecules induce immunosuppression in the tumour microenvironment. An immunosuppressive enzyme, indoleamine 2,3-dioxygenase (IDO/IDO1), facilitates immune escape in several malignant tumours, including osteosarcoma. Upregulation of IDO establishes a tolerogenic environment in the tumour and the tumour-draining lymph nodes. IDO-induced downregulation of effector T-cells and upregulation of local regulatory T-cells creates immunosuppression and promotes metastasis. Observations: Osteosarcoma is the most common bone tumour characterised by immature bone formation by the tumour cells. Almost 20% of osteosarcoma patients present with pulmonary metastasis at the time of diagnosis. The improvement in therapeutic modalities for osteosarcoma has been in a stagnant phase for two decades. Therefore, the development of novel immunotherapeutic targets for osteosarcoma is emergent. High IDO expression is associated with metastasis and poor prognosis in osteosarcoma patients. Conclusion and Relevance: At present, only a few studies are available describing IDO's role in osteosarcoma. This review describes the prospects of IDO not only as a prognostic marker but also as an immunotherapeutic target for osteosarcoma.

Exploring the relationship between abnormally high expression of NUP205 and the clinicopathological characteristics, immune microenvironment, and prognostic value of lower-grade glioma.

Nuclear pore complex (NPC) is a major transport pivot for nucleocytoplasmic molecule exchange. Nucleoporin 205 (NUP205)-a main component of NPC-plays a key regulatory role in tumor cell proliferation; however, few reports document its effect on the pathological progression of lower-grade glioma (LGG). Therefore, we conducted an integrated analysis using 906 samples from multiple public databases to explore the effects of NUP205 on the prognosis, clinicopathological characteristics, regulatory mechanism, and tumor immune microenvironment (TIME) formation in LGG. First, multiple methods consistently showed that the mRNA and protein expression levels of NUP205 were higher in LGG tumor tissue than in normal brain tissue. This increased expression was mainly noted in the higher WHO Grade, IDH-wild type, and 1p19q non-codeleted type. Second, various survival analysis methods showed that the highly expressed NUP205 was an independent risk indicator that led to reduced survival time of patients with LGG. Third, GSEA analysis showed that NUP205 regulated the pathological progress of LGG via the cell cycle, notch signaling pathway, and aminoacyl-tRNA biosynthesis. Ultimately, immune correlation analysis suggested that high NUP205 expression was positively correlated with the infiltration of multiple immune cells, particularly M2 macrophages, and was positively correlated with eight immune checkpoints, particularly PD-L1. Collectively, this study documented the pathogenicity of NUP205 in LGG for the first time, expanding our understanding of its molecular function. Furthermore, this study highlighted the potential value of NUP205 as a target of anti-LGG immunotherapy.

Indoleamine 2,3-dioxygenase 1 promotes osteosarcoma progression by regulating tumor-derived exosomal miRNA hsa-miR-23a-3p.

Background: Osteosarcoma (OS) is the most common primary malignant tumor originating in bone. Immunosuppressive enzyme indoleamine 2,3-dioxygenase 1 (IDO1) participates in tumor immune tolerance and promotes tumor progression, while the study of IDO1 in OS is limited. Methods: Immunohistochemistry analysis was performed to test the expression of IDO1 and Ki67. The relationship between IDO1 or Ki67 positive count and clinical stage of the patient was analyzed. Laboratory test indexes including serum alkaline phosphatase (ALP), lactate dehydrogenase (LDH), white blood cell (WBC) count and C-reactive protein (CRP) at diagnosis of OS patients were collected. The relationship between positive count of IDO1 and Ki67 or laboratory test indexes was analyzed by Pearson's correlation analysis. IDO1 stably overexpressed cell lines of these cells (MG63 OE, 143B OE and hFOB1.19 OE) were constructed and validated by Western blot and Elisa. Exosomes were isolated from conditioned culture media of these cells and were identified by Zetaview nanoparticle tracking analyzer. Next-generation sequencing was conducted to identify miRNAs enriched in exosomes. Differentially expressed miRNAs (DE miRNAs) were verified in clinical samples and cell lines by qPCR. Biological processes and cell components analysis of DE miRNAs was conducted by GO enrichment analysis using the protein interaction network database. Results: Immunosuppressive enzyme IDO1 was highly expressed in tumor tissues. 66.7% (6/9) of the tissues showed moderately or strongly positive immunostaining signal of IDO1, and 33.3% (3/9) were weakly positive. The expression of IDO1 was positively related to Ki67 and associated with prognostic-related clinical features of OS patients. Overexpression of IDO1 significantly affected the exosome-derived miRNA subsets from MG63, 143B and hFOB1.19 cells. A total of 1244 DE miRNAs were identified, and hsa-miR-23a-3p was further screened as key DE miRNA involved in the progression of OS. GO analysis of target genes of the DE miRNA results showed that target enrichment in the functions of immune regulation and tumor progression. Discussion: Our results indicate that IDO1 has the potential to promote the progression of OS that is related to miRNAs mediated tumor immunity. Targeting IDO1-mediated hsa-miR-23a-3p may be a potential therapeutic strategy for OS treatment.

CD38 as a multifaceted immunotherapeutic target in CLL.

CD38 is a glycoprotein expressed on chronic lymphocytic leukemia (CLL) cells, which functions to amplify B-cell receptor signaling and regulate nicotinamide adenine dinucleotide metabolism. Increased CD38 expression on CLL cells is associated with an unfavorable disease course, resulting in shorter overall survival. While the role of CD38 as a negative prognostic marker in CLL has been established for over two decades, the therapeutic benefit to be derived by patients from its inhibition has, till date remained an unresolved subject. With the development of high-affinity anti-CD38 targeting drugs, tremendous insight has been gained on which functions of CD38 are detrimental to CLL cell survival as well as the mechanisms of leukemic cell death engaged by these anti-CD38 agents. The current review attempts to resolve how the enzyamtic and receptorial functions of CD38 contribute to CLL pathogenesis, our ability to exploit these functions for immunotherapeutic effect and development of novel strategies targeting CD38.

A correlation study of adhesion G protein-coupled receptors as potential therapeutic targets in Uterine Corpus Endometrial cancer.

BACKGROUND: Adhesion G protein-coupled receptors (adhesion GPCRs), as a member of the G protein-coupled receptors (GPCRs) superfamily, have gradually entered the field of vision of researchers. The structure, function, and involvement of adhesion GPCRs in cancer development have been discussed in a series of papers. Uterine Corpus Endometrial Carcinoma (UCEC) isa malignanttumorofendometrium epithelial, whichis alsooneofthemostcommonfemalereproductivesystemtumors, but there are few pieces of research related to adhesion GPCRs in UCEC. METHODOLOGY: In the current study, the UALCAN, GEPIA, Kaplan-Meier Plotter, MethSurv, SurvivalMeth, cBioPortal, String, GeneMANIA, DAVID, TRRUST, and Timer databases were used to examine the expression patterns and probable roles of adhesion GPCR family in UCEC. RESULTS: The expression levels of ADGRC1, ADGRC3, ADGRE1, ADGRF1, ADGRF2, ADGRF3, ADGRF4, ADGRG1, ADGRG5, ADGRG7, and ADGRV1 were significantly elevated in UCEC tissues, and the expression of ADGRC3 and ADGRF1 was significantly correlated with the pathological stage of UCEC. In patients with UCEC, ADGRA3, ADGRB1, ADGRB2, ADGRB3, ADGRC3, ADGRD2, ADGRF1, ADGRF2, ADGRF4, ADGRG1, ADGRG2, ADGRG4, ADGRG6, ADGRG7, ADGRL1, ADGRL2, and ADGRL3 had played important roles in patients' overall survival (OS), with a high expression suggesting shorter OS; while high levels of ADGRC2, ADGRD2, ADGRG7, and ADGRL2 suggested lower relapse-freesurvival (RFS). Furthermore, the prognostic value of the adhesion GPCRs gene individual CpG, as well as DNA methylation, was also analyzed; however, DNA methylation profiling demonstrated no significant correlation between the methylation level of adhesion GPCRs and the prognosis. The neighbor gene interaction analysis and enrichment analysis were also implemented to detect the possible mechanism. In addition, we found a correlation between the adhesion GPCRs and immune infiltrating cells, and the Cox proportional risk model of adhesion GPCRs with six immune cells showed that ADGRA1, ADGRF1, and ADGRG3 were closely connected with the clinical manifestations of UCEC patients. CONCLUSION: The adhesion GPCRs, especially ADGRF1, might be used as immunotherapeutic targets and prognostic markers of UCEC.

CC Chemokine Receptors in Lung Adenocarcinoma: The Inflammation-Related Prognostic Biomarkers and Immunotherapeutic Targets.

BACKGROUND: Lung adenocarcinoma (LUAD) is the most common type of lung cancer with a high incidence and increased mortality. CC chemokine receptors were participating in the modulation of the tumor microenvironment and involved in carcinogenesis and tumor development. However, the potential mechanistic values of CC chemokine receptors as clinical biomarkers and therapeutic targets in LUAD have not been fully clarified. METHODOLOGY: ONCOMINE, UALCAN, GEPIA, Kaplan-Meier Plotter, SurvExpress, MethSurv, SurvivalMeth, cBioPortal, String, GeneMANIA, DAVID, Metascape, TRRUST, LinkedOmics, and Timer were applied in this work. RESULTS: The transcriptional levels of CCR1/10 in LUAD tissues were significantly reduced while the transcriptional levels of CCR3/6/7/8 were significantly elevated, and the expression of CCR1 was the highest in LUAD among these CC chemokine receptors. A significant correlation was found between the expression of CCR2/4/6/7 and the pathological stage of LUAD patients. There were significant associations between CCR2/3/4/5/6/10 expression levels and OS in LUAD, and LUAD patients with high transcriptional levels of CCR3/4 had inferior first-progression survival. In addition, the prognostic values of CC chemokine receptors signature in LUAD were explored in three independent cohorts, the high-risk group displayed unfavorable OS compared with the low-risk group, and the LUAD cases in the high-risk group also suffered inferior RFS than that in the low-risk group. And for the prognostic value of the DNA methylation of CC chemokine receptors, we found 1 CpG of CCR2, 2 CpGs of CCR3, 1 CpG of CCR4, 3 CpGs of CCR6, 3 CpGs of CCR7, 1 CpG of CCR8, and 3 CpGs of CCR9 were significantly associated with prognosis in LUAD patients. However, the DNA methylation signature analysis showed there was no statistically significant association between the high- and low-risk group. For potential mechanism, the neighbor gene networks, interaction analyses, functional enrichment analyses of CC chemokine receptors in LUAD were performed, the transcription factor targets, kinase targets, and miRNA targets of CC chemokine receptors were also identified in LUAD. We also found significant correlations among CC chemokine receptors expression and the infiltration of immune cells, the tumor infiltration levels among LUAD with different somatic copy number alterations of these chemokine receptors were also assessed. Moreover, the Cox proportional hazard model showed that CCR1/2/10, B_cell, CD4_Tcell were significantly related to the clinical outcome of LUAD patients. CONCLUSION: CC chemokine receptors might serve as immunotherapeutic targets and prognostic biomarkers in LUAD.

TCL1 as a hub protein associated with the PI3K/AKT signaling pathway in diffuse large B-cell lymphoma based on proteomics methods.

This study aimed to investigate the hub protein related to the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT) signaling pathway in diffuse large B-cell lymphoma (DLBCL). We used proteomics methods (iTRAQ) to explore the differentially expressed proteins in the non-germinal center B-cell -like (non-GCB) DLBCL in our previous study. In this study, a total of 137 formalin-fixed paraffin-embedded DLBCL tissue samples were analyzed via immunohistochemistry to verify the expression of TCL1, AKT1 + 2+3, IKKß and to determine the differentially expressed proteins associated with the PI3K/AKT signaling pathway. Spearman correlation was used to analyze the relationship between these proteins, and survival analysis was used to investigate their effects on prognosis. Immunohistochemistry analysis indicated that TCL1, AKT1 + 2+3, and IKKß were highly positively expressed in DLBCL. Results showed that the expression of TCL1 was related to ethnicity (p = 0.022), primary site (p = 0.045), Ann Arbor stage (p = 0.037), the International Prognostic Index (p = 0.005), ß2-microglobulin (p = 0.030), BCL2 expression (p < 0.001), and Ki-67 expression (p = 0.008). A positive correlation was found between TCL1 and AKT1 + 2+3 (p < 0.001; r = 0.475). A positive correlation was also found between AKT1 + 2+3 and IKKß (p < 0.001; r = 0.342). In survival analysis, anemia, non-treatment with R­CHOP, positive TCL1 expression, and Ki-67 expression≥50% independently predicted short progression-free survival and overall survival in the total cohort (p < 0.05). Thus, TCL1 as a hub protein is associated with the PI3K/AKT signaling pathway in DLBCL. TCL1 expression indicated a poor prognosis in patients with DLBCL. With further studies, TCL1 may be established as a reliable prognostic biomarker and potential immunotherapeutic target for improving therapeutic efficacy for DLBCL in the future.

Functional and Clinical Characterization of Tumor-Infiltrating T Cell Subpopulations in Hepatocellular Carcinoma.

Tumor-infiltrating T-lymphocytes are defined as T-lymphocytes that infiltrated into tumor tissues; however, their composition, clinical significance, and underlying mechanism in hepatocellular carcinoma (HCC) and adjacent non-tumor tissues are still not completely understood. Herein, we collected marker genes of T cell subpopulations from a previous study and estimated their relative infiltrating levels in HCC and adjacent non-tumor tissues. Specifically, the infiltrating levels of all the T cells were significantly reduced in HCC as compared with non-tumor tissues. Unsupervised clustering of the HCC samples by the T cell infiltrating levels revealed that the HCC samples could be clearly classified into two groups. The driver genes, including PTK2B, ATM, PIK3C2B, and KIT, and several CNAs were observed to be associated with reduced T cell infiltrating levels. Particularly, deletion of TP53 more frequently occurred in low T cell infiltration HCC samples and resulted in its downregulation and cell cycle progression, indicating that cell cycle progression was closely associated with reduced T cell infiltration. In contrast, for the samples with high infiltration T cells, its immune evasion might be regulated by the immune checkpoint regulators, such as PD-1/PD-L1 and CTLA4. Moreover, Olaparib, one of the PARP inhibitors, and immune checkpoint inhibitors might be therapeutic candidates for the samples from the two T cell infiltrating clusters. Clinically, the tumor-infiltrating levels of cytotoxic CD4 cell, Mucosal associated invariant T (MAIT) cell, and exhausted CD8+ T cell might be used as predictors for vascular invasion, recurrence, and overall survival. Collectively, we systematically evaluated the clinical significance and potential molecular mechanisms of tumor-infiltrating T cell subpopulations in hepatocellular carcinoma, which might broaden our insights into the immunological features of HCC and provide potential immunotherapeutic targets.

Parasite-Produced MIF Cytokine: Role in Immune Evasion, Invasion, and Pathogenesis.

Protozoan parasites represent a major threat to health and contribute significantly to morbidity and mortality worldwide, especially in developing countries. This is further compounded by lack of effective vaccines, drug resistance and toxicity associated with current therapies. Multiple protozoans, including Plasmodium, Entamoeba, Toxoplasma, and Leishmania produce homologs of the cytokine MIF. These parasite MIF homologs are capable of altering the host immune response during infection, and play a role in immune evasion, invasion and pathogenesis. This minireview outlines well-established and emerging literature on the role of parasite MIF homologs in disease, and their potential as targets for therapeutic and preventive interventions.

Whole-exome sequencing predicted cancer epitope trees of 23 early cervical cancers in Chinese women.

Emerging evidence suggest that the heterogeneity of cancer limits the efficacy of immunotherapy. To search for optimal therapeutic targets for enhancing the efficacy, we used whole-exome sequencing data of 23 early cervical tumors from Chinese women to investigate the hierarchical structure of the somatic mutations and the neo-epitopes. The putative neo-epitopes were predicted based on the mutant peptides' strong binding with major histocompatibility complex class I molecules. We found that each tumor carried an average of 117 mutations and 61 putative neo-epitopes. Each patient displayed a unique phylogenetic tree in which almost all subclones harbored neo-epitopes, highlighting the importance of individual neo-epitope tree in determination of immunotherapeutic targets. The alterations in FBXW7 and PIK3CA, or other members of the significantly altered ubiquitin-mediated proteolysis and extracellular matrix receptor interaction related pathways, were proposed as the earliest changes triggering the malignant progression. The neo-epitopes involved in these pathways, and located at the top of the hierarchy tree, might become the optimal candidates for therapeutic targets, possessing the potential to mediate T-cell killing of the descendant cells. These findings expanded our understanding in early stage of cervical carcinogenesis and offered an important approach to assist optimizing the immunotherapeutic target selection.