PD-L2 based immune signature confers poor prognosis in HNSCC.
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ABSTRACT:
SUBMITTER: Qiao Y
PROVIDER: S-EPMC8344752 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundProgrammed cell death protein 1 (PD-1) is a key immune checkpoint that regulates peripheral tolerance and protects against autoimmunity. Programmed death ligand-2 (PD-L2) is a less studied ligand to PD-1 and has yet to be fully explored, especially in pancreatic ductal adenocarcinoma (PDAC).MethodsIn this study, we performed immunohistochemistry to detect the PD-L2, CD3, CD8, transforming growth factor-β2 (TGF-β2) and FOXP3 levels in paraffin sections from 305 patients with resected PDAC as a training set. Expression levels of intratumoral and stromal immune markers were compared in relation to survival using Kaplan-Meier curves, random survival forest model and survival tree analysis. A multivariable Cox proportional-hazards model of associated markers was used to calculate the risk scores.ResultsPD-L2 was expressed in 71.5% of PDAC samples and showed strong correlations with CD3+, CD8+ T cells and FOXP3+ regulatory T cell densities. High levels of intratumoral PD-L2 and FOXP3 were related to poor survival; only stromal FOXP3 overexpression was associated with worse prognosis. Four patterns generated from survival tree analysis demonstrated that PD-L2lowstromalFOXP3low patients had the longest survival, while PD-L2highintratumoralCD3low patients had the shortest survival (P < 0.001). The area under the curve was 0.631(95% confidence interval (CI): 0.447-0.826) for the immune marker-based signature and 0.549 (95% CI: 0.323-0.829; P < 0.001) for the clinical parameter-based signature, which was consistent with the results in the validation set including 150 patients (P < 0.001). A higher risk score indicated shorter survival and could serve as an independent prognostic factor. PD-L2 was also showed associated with TGF-β2 and other immune molecules based on bioinformatics analysis.ConclusionsOur work highlighted PD-L2 as a promising immunotherapeutic target with prognostic value combined with complex tumor infiltrating cells in PDAC.
| S-EPMC6716876 | biostudies-literature
Project description:Head and neck squamous cell carcinoma (HNSCC) is an invasive malignancy with high worldwide mortality. Growing evidence has indicated a pivotal correlation between HNSCC prognosis and immune signature. This study investigated an immune-related gene pairs (IRGPs) signature to predict the prognostic value of HNSCC patients. We constructed IRGPs via integrating multiple IRG expression data sets. Moreover, we established the predictive model base on the IRGPs for HNSCC, and utilized multidimensional bioinformatics methods to validate the robustness of prognostic value of the IRGPs signature. In addition, we explored the relationship between the IRGPs model and immune status. Seventeen IRGPs signature was built as the predictive model which predicted prognosis independently and reliably for HNSCC. Compared to the high-risk group, the low-risk group demonstrated a distinctly favorable prognosis including overall survival (OS), disease-specific survival (DSS), and progression-free survival (PFS). The low-risk group showed higher-immune score and lower-tumor purity than the high-risk group. In addition, the low-risk group exhibited higher expression of Programmed cell death 1 ligand 1 (PD-L1) and Microsatellite instability (MSI) score, and lower expression of Tumor Immune Dysfunction and Exclusion (TIDE), which indicated the low-risk group was much more sensitive to immunotherapy. Lastly, the IRGs signature has achieved a higher accuracy than clinical properties for estimation of survival. The IRGPs model is an independent biomarker for estimating the prognosis, and could be also used to predict immunotherapeutic response in HNSCC patients. These findings may provide new ideas for novel biomarkers and may be helpful to formulate personalized immunotherapy strategy.
| S-EPMC7689340 | biostudies-literature
Project description:CD73 is a cell surface immunosuppressive enzyme involved in tumor progression and metastasis. While patients whose cancer cells express elevated CD73 are typically associated with an unfavorable outcome, the clinical impact of CD73 expression in patients with Head and neck squamous cell carcinoma (HNSCC) remains unclear. In the present study, we investigated the prognostic significance of CD73 in HNSCC using gene and protein expression analyses. Our results demonstrate that high levels of CD73 are significantly associated with reduced overall survival in patients with HNSCC. We also investigated the functional role of CD73 in vitro and demonstrated that CD73 promotes HNSCC migration and invasion through adenosine A3R stimulation and the activation of EGF/EGFR signaling. Moreover, in vivo xenograft studies demonstrated that CD73 promotes tumorigenesis. In conclusion, our study highlights a role for CD73 as a poor prognostic marker of patient survival and also as a candidate therapeutic target in HNSCCs.
| S-EPMC5308683 | biostudies-literature
Project description:Anti-programmed cell death-1 (PD-1) antibodies has been approved to treat HCC. Some PD-1 ligands (PD-L1 and PD-L2) negative tumors respond to treatment of anti-PD-1 antibodies, and this fact may be caused by the expression of PD-1 ligands on non-tumor cells. PD-L1 was recently found to be expressed on CD14+ cells from cancer patients. We investigate PD-1 ligands expression on CD14+ cells of patients with HCC and the role of CD14+ cells in an antitumor response. In this study, 87 patients diagnosed with HCC were enrolled. CD14+ cells from patients with HCC expressed PD-L1 (4.5-95.5%) and PD-L2 (0.2-95.0%). According to cut-off values, we classified patients as those either with PD-L1+PD-L2+CD14+ cells or other types of CD14+ cells. The overall survival of patients with PD-L1+PD-L2+CD14+ cells was shorter than that of patients with other types of CD14+ cells (p?=?0.0023). PD-L1+PD-L2+CD14+ cells produced IL-10 and CCL1, and showed little tumoricidal activity against HepG2 cells. The tumoricidal activity of CD8+ cells from patients with PD-L1+PD-L2+CD14+ cells were suppressed by co-cultivation with CD14+ cells from the syngeneic patient. Furthermore, anti-PD-1 antibody restored their tumoricidal activity of CD8+ cells. In conclusion, some patients with HCC have PD-L1+PD-L2+CD14+ cells that suppress their antitumor response. These inhibitory functions of CD14+ cells may be associated with a poor prognosis in these patients.
| S-EPMC7316832 | biostudies-literature
Project description:Viruses often subvert antiviral immune responses by taking advantage of inhibitory immune signaling. We investigated if hantaviruses use this strategy. Hantaviruses cause viral hemorrhagic fever (VHF) which is associated with strong immune activation resulting in vigorous CD8+ T cell responses. Surprisingly, we observed that hantaviruses strongly upregulate PD-L1 and PD-L2, the ligands of checkpoint inhibitor programmed death-1 (PD-1). We detected high amounts of soluble PD-L1 (sPD-L1) and soluble PD-L2 (sPD-L2) in sera from hantavirus-infected patients. In addition, we observed hantavirus-induced PD-L1 upregulation in mice with a humanized immune system. The two major target cells of hantaviruses, endothelial cells and monocyte-derived dendritic cells, strongly increased PD-L1 and PD-L2 surface expression upon hantavirus infection in vitro. As an underlying mechanism, we found increased transcript levels whereas membrane trafficking of PD-L1 was not affected. Further analysis revealed that hantavirus-associated inflammatory signals and hantaviral nucleocapsid (N) protein enhance PD-L1 and PD-L2 expression. Cell numbers were strongly reduced when hantavirus-infected endothelial cells were mixed with T cells in the presence of an exogenous proliferation signal compared to uninfected cells. This is compatible with the concept that virus-induced PD-L1 and PD-L2 upregulation contributes to viral immune escape. Intriguingly, however, we observed hantavirus-induced CD8+ T cell bystander activation despite strongly upregulated PD-L1 and PD-L2. This result indicates that hantavirus-induced CD8+ T cell bystander activation bypasses checkpoint inhibition allowing an early antiviral immune response upon virus infection.
| S-EPMC6287426 | biostudies-other
Project description:Objectives: Head and neck squamous cell carcinoma (HNSCC) is the most common malignancy of the head and neck. However, the molecular mechanisms governing the development of HNSCC have not been fully elucidated. Materials and Methods: Differentially expressed genes (DEGs) were screened out from The Cancer Genome Atlas (TCGA) and GSE23036 datasets. Weighted gene coexpression network analysis (WGCNA) was used to reveal the correlations among genes and to search for significantly correlated gene modules. The expression levels of genes in HNSCC and normal samples according to antibody-based detected methods was assessed by utilizing the Human Protein Atlas (HPA). The impact of the selected hub genes on the prognosis of HNSCC patients was assessed by analysing immunohistochemistry (IHC) and immunofluorescence (IF) expression levels and clinical data. Results: Twenty-four genes positively correlated with tumour status and 15 genes negatively correlated with tumour status were screened out by WGCNA. PLAU and LAMC2 were associated with a poor prognosis in patients with HNSCC and were finally screened out and verified by GEPIA and HPA database analysis. Immunohistochemistry of samples collected from 175 patients with HNSCC and subsequent statistical analysis also showed that PLAU and LAMC2 were associated with a poor prognosis in patients with HNSCC, and the levels of these two factors were positively correlated. The expression and co-localization of PLAU and LAMC2 in HNSCC tissues were confirmed by double immunofluorescence labeling. Conclusions: There was a positive correlation between PLAU and LAMC2 expression in HNSCC samples, and PLAU and LAMC2 might be independent prognostic biomarkers for HNSCC.
| S-EPMC10266254 | biostudies-literature
Project description:BackgroundPancreatic Cancer is one of the most lethal cancers, with less than 8% of patients surviving 5 years following diagnosis. The last 40 years have seen only small incremental improvements in treatment options, highlighting the continued need to better define the cellular and molecular pathways contributing to therapy response and patient prognosis.MethodsWe combined CRISPR, shRNA and flow cytometry with mechanistic experiments using a KrasG12Dp53R172H mouse model of pancreatic cancer and analysis of publicly available human PDAC transcriptomic datasets.ResultsHere, we identify that expression of the immune checkpoint, Programmed Death Ligand 2 (PD-L2), is associated with poor prognosis, tumour grade, clinical stage and molecular subtype in patients with Pancreatic Ductal Adenocarcinoma (PDAC). We further show that PD-L2 is predominantly expressed in the stroma and, using an orthotopic murine model of PDAC, identify cancer cell-intrinsic Focal Adhesion Kinase (FAK) signalling as a regulator of PD-L2 stromal expression. Mechanistically, we find that FAK regulates interleukin-6, which can act in concert with interleukin-4 secreted by CD4 T-cells to drive elevated expression of PD-L2 on tumour-associated macrophages, dendritic cells and endothelial cells.ConclusionsThese findings identify further complex heterocellular signalling networks contributing to FAK-mediated immune suppression in pancreatic cancer.
| S-EPMC9643373 | biostudies-literature
Project description:Calpains are a family of intracellular cysteine proteases involved in various biological processes. Previously, the family was identified to have abnormal expression in several types of malignant tumor. Calpain 6 was less well known; however, it was recently identified to be involved in the carcinogenesis of certain types of malignant tumor. However, the expression of calpain 6 in head and neck squamous cell carcinoma (HNSCC) remains unclear. A total of six datasets from the Gene Expression Omnibus (GEO) was analyzed and an association between calpain 6 expression levels and HNSCC was identified, with the expression of calpain 6 observed to be significantly decreased in HNSCC (P<0.01). However, the expression of calpain 6 may vary between distinct tumor stages of HNSCC. Furthermore, calpain 6 expression was positively associated with the survival rate in patients with HNSCC (P<0.05), with increased expression of calpain 6 associated with an improved survival outcome. Calpain 6 expression was analyzed using an HNSCC tissue microarray and these results were consistent with the statistical analysis of the bioinformatics data from the GEO, indicating that calpain 6 may be a tumor suppressor protein in HNSCC.
| S-EPMC5403261 | biostudies-literature
Project description:PurposeThe majority deaths of cancer patients are related to metastasis, thus genes associated with cell motility interest us. SPOCK1 was elected by data mining and serial evaluation. In addition, SPOCK1 has been reported to be highly expressed in different human cancers and been related to adverse outcomes. Therefore, we validate its prognostic significance in urothelial carcinoma (UC).Materials and methodsReal-time RT-PCR assay was used to detect SPOCK1 transcript level in 27 urinary tract urothelial carcinoma (UTUC) and 27 urinary bladder urothelial carcinoma (UBUC) samples. Immunohistochemistry evaluated by H-score determined SPOCK1 expressions in 340 UTUCs and 295 UBUCs. The transcript and protein expression were correlated with clinicopathological features. Further evaluations of the prognostic significance of SPOCK1 for disease-specific survival (DSS) and metastasis-free survival (MeFS) were analyzed.ResultsThe expressions of SPOCK1 in UC were higher than those in normal urothelium by immunohistochemistry. The statistical analysis of clinicopathologic characteristics and immunohistochemistry showed that the higher expression of SPOCK1 was correlated to pT status (P<0.001), lymph node metastasis (UTUC, P=0.006; UBUC, P=0.033), higher histological grade (UTUC, P<0.001; UBUC, P<0.001), vascular invasion (UTUC, P<0.001; UBUC, P<0.001), perineurial invasion (UTUC, P<0.001; UBUC, P=0.001) and frequent mitosis (UTUC, P<0.001; UBUC, P=0.001). The prognosis of SPOCK1 of UC showed high SPOCK1 expression had significantly worse DSS and MeFS.ConclusionsThe investigation demonstrated that the higher expression of SPOCK1 correlates with a poor prognosis in UC.
| S-EPMC4749368 | biostudies-literature
Project description:BackgroundCombination therapy has been explored for advanced head and neck squamous cell carcinoma (HNSCC) owing to the limited efficacy of anti-epidermal growth factor receptor (EGFR) therapy. Increased expression and glycosylation of immune checkpoint molecules in tumors are responsible for cetuximab therapy refractoriness. The role of programmed death ligand 2 (PD-L2), a ligand of PD-1, in the immune function is unclear. Here, we examined the regulatory mechanism of PD-L2 glycosylation and its role in antitumor immunity and cetuximab therapy.MethodsSingle-cell RNA sequencing and immunohistochemical staining were used to investigate PD-L2 expression in cetuximab-resistant/sensitive HNSCC tissues. The mechanism of PD-L2 glycosylation regulation was explored in vitro. The effects of PD-L2 glycosylation on immune evasion and cetuximab efficacy were verified in vitro and using mice bearing orthotopic SCC7 tumors.ResultsThe PD-L2 levels were elevated and N-glycosylated in patients with cetuximab-resistant HNSCC. Glycosylated PD-L2 formed a complex with EGFR, which resulted in the activation of EGFR/signal transducer and activator of transcription 3 (STAT3) signaling and decreased the cetuximab binding affinity to EGFR. The N-glycosyltransferase fucosyltransferase (FUT8), a transcriptional target of STAT3, was required for PD-L2 glycosylation. Moreover, glycosylation modification stabilized PD-L2 by blocking ubiquitin-dependent lysosomal degradation, which consequently promoted its binding to PD-1 and immune evasion. Inhibition of PD-L2 glycosylation using Stattic, a specific STAT3 inhibitor, or PD-L2 mutation blocking its binding to FUT8, increased cytotoxic T lymphocyte activity and augmented response to cetuximab.ConclusionsIncreased expression and glycosylation of PD-L2 in tumors are an important mechanism for cetuximab therapy refractoriness. Thus, the combination of PD-L2 glycosylation inhibition and cetuximab is a potential therapeutic strategy for cancer.
| S-EPMC8547513 | biostudies-literature