Gene code CD274/PD-L1: from molecular basis toward cancer immunotherapy.
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ABSTRACT:
SUBMITTER: Fabrizio FP
PROVIDER: S-EPMC6299305 | biostudies-literature | 2018
REPOSITORIES: biostudies-literature
Publications
Gene code <i>CD274/PD-L1</i>: from molecular basis toward cancer immunotherapy.
Fabrizio Federico Pio FP Trombetta Domenico D Rossi Antonio A Sparaneo Angelo A Castellana Stefano S Muscarella Lucia Anna LA
Therapeutic advances in medical oncology 20181217
The programmed death 1 receptor (PD-1) and its ligand (PD-L1) are key molecules of immune checkpoint mechanisms in cancer and actually represent one of the main targets of immunotherapy. The predictive and prognostic values of PD-L1 expression alone in cancer patients is currently under debate due to the methodological assessment of PD-L1 expression and its temporal variations. Better detailed studies about the molecular basis of immunotherapy biomarkers are necessary. Here we summarize the curr ...[more]
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Project description:Purpose: Programmed death ligand-1 (PD-L1), encoded by the CD274 gene, is a target for immune checkpoint blockade; however, little is known about genomic CD274 alterations. A subset of small-cell lung cancer (SCLC) exhibits increased copy number of chromosome 9p24, on which CD274 resides; however, most SCLCs show low expression of PD-L1. We therefore examined whether CD274 is a target of recurrent genomic alterations.Experimental Design: We examined somatic copy number alterations in two patient cohorts by quantitative real-time PCR in 72 human SCLC cases (cohort 1) and SNP array analysis in 138 human SCLC cases (cohort 2). Whole-genome sequencing revealed the detailed genomic structure underlying focal amplification. PD-L1 expression in amplified cases from cohorts 1 and 2 was further examined by transcriptome sequencing and immunohistochemical (IHC) staining.Results: By examining somatic copy number alterations in two cohorts of primary human SCLC specimens, we observed 9p24 copy number gains (where CD274 resides) and focal, high-level amplification of CD274 We found evidence for genomic targeting of CD274, suggesting selection during oncogenic transformation. CD274 amplification was caused by genomic rearrangements not affecting the open reading frame, thus leading to massively increased CD274 transcripts and high level expression of PD-L1.Conclusions: A subset (4/210, 1.9%) of human SCLC patient cases exhibits massive expression of PD-L1 caused by focal amplification of CD274 Such tumors may be particularly susceptible to immune checkpoint blockade. Clin Cancer Res; 23(5); 1220-6. ©2016 AACR.
| S-EPMC6329376 | biostudies-literature
Project description:OBJECTIVE:Evidence suggests that CD274 (programmed death-ligand 1, B7-H1) immune checkpoint ligand repress antitumour immunity through its interaction with the PDCD1 (programmed cell death 1, PD-1) receptor of T lymphocytes in various tumours. We hypothesised that tumour CD274 expression levels might be inversely associated with T-cell densities in colorectal carcinoma tissue. DESIGN:We evaluated tumour CD274 expression by immunohistochemistry in 823 rectal and colon cancer cases within the Nurses' Health Study and Health Professionals Follow-up Study. We conducted multivariable ordinal logistic regression analyses to examine the association of tumour CD274 expression with CD3+, CD8+, CD45RO (PTPRC)+ or FOXP3+ cell density in tumour tissue, controlling for potential confounders including tumour status of microsatellite instability (MSI), CpG island methylator phenotype, long interspersed nucleotide element-1 methylation level and KRAS, BRAF and PIK3CA mutations. RESULTS:CD274 expression in tumour cells or stromal cells (including immune cells) was detected in 731 (89%) or 44 (5%) cases, respectively. Tumour CD274 expression level correlated inversely with FOXP3+ cell density in colorectal cancer tissue (outcome) (ptrend=0.0002). For a unit increase in outcome quartile categories, multivariable OR in the highest (vs lowest) CD274 expression score was 0.22 (95% CI 0.10 to 0.47). Tumour CD274 expression was inversely associated with MSI-high status (p=0.001). CD274 expression was not significantly associated with CD3+, CD8+ or CD45RO+ cell density, pathological lymphocytic reactions or patient survival prognosis. CONCLUSIONS:Tumour CD274 expression is inversely associated with FOXP3+ cell density in colorectal cancer tissue, suggesting a possible influence of CD274-expressing carcinoma cells on regulatory T cells in the tumour microenvironment.
| S-EPMC5097696 | biostudies-literature
Project description:This study evaluates promoter methylation of the programmed cell death ligand 1 (PD-L1) as a biomarker in a cohort of 383 colorectal cancer patients. PD-L1 methylation (mPD-L1) was inversely correlated with PD-L1 mRNA expression (p = 0.001) and was associated with significantly shorter overall survival (OS, p = 0.003) and recurrence-free survival (RFS, p < 0.001). In age-stratified multivariate Cox proportional hazards analyses including sex, tumor, nodal, distant metastasis categories, microsatellite instability (MSI)-status, and PD-L1 mRNA, mPD-L1 is classified as an independent prognostic factor (OS: p = 0.030; RFS: p < 0.001). Further studies are needed to evaluate PD-L1 methylation as a biomarker for response prediction of immunotherapies targeting the PD-1/PD-L1 axis.
| S-EPMC5283627 | biostudies-literature
Project description:The effects of non-amplification short variant (SV) mutations in CD274 (programmed death-ligand 1 (PD-L1)) on PD-L1 protein expression and immune checkpoint inhibitors (ICPIs) therapy are unknown. Here, we present a retrospective analysis of CD274 mutations detected by comprehensive genomic profiling (CGP) and correlate these results with tumor-cell PD-L1 immunohistochemistry (IHC)-based expression assessment to better understand the relationship between mutations and protein expression of PD-L1. CGP was performed on hybridization-captured, adaptor ligation-based libraries using DNA and/or RNA extracted from 314,631 tumor samples that were sequenced for up to 406 cancer-related genes and select gene rearrangements. PD-L1 IHC was performed on a subset of cases (n=58,341) using the DAKO 22C3 PD-L1 IHC assay and scored with the tumor proportion score (TPS). Overall, the prevalence of CD274 SV mutations was low (0.3%, 1081/314,631) with 577 unique variants. The most common CD274 SV mutations were R260H (n=51), R260C (n=18), R125Q (n=12), C272fs*13 (n=11), R86W (n=10), and R113H (n=10). The prevalence of CD274 mutations varied depending on tumor type with diffuse large B-cell lymphoma (1.9%, 19/997), cutaneous squamous cell carcinoma (1.6%, 14/868), endometrial adenocarcinoma (1.0%, 36/3740), unknown primary melanoma (0.9%, 33/3679), and cutaneous melanoma (0.8%, 32/3874) having the highest frequency of mutations. Of the R260H cases concurrently tested with PD-L1 IHC, most (81.8%, 9/11) had no PD-L1 expression, which contrasts to the five E237K cases where most (80%, 4/5) had PD-L1 expression. In addition, we saw a significantly lower level of PD-L1 expression in samples with a clonal truncating variant (nonsense or frameshift indel) when compared with samples with a subclonal truncating variants (mean: TPS=1 vs TPS=38; p<0.001), and also in clonal versus subclonal missense mutations (mean: TPS=11 vs TPS=22, respectively; p=0.049) CONCLUSIONS: We defined the landscape of CD274 mutations in a large cohort of tumor types that can be used as a reference for examining CD274 mutations as potential resistance biomarkers for ICPI. Furthermore, we presented novel data on the correlation of CD274 mutations and PD-L1 protein expression, providing important new information on the potential functionality of these mutations and can serve as a basis for future research.
| S-EPMC8207995 | biostudies-literature
Project description:Immunomodulatory therapies, targeting the immune checkpoint receptor-ligand complex PD-1/PD-L1 have shown promising results in early phase clinical trials in solid malignancies, including carcinomas of the head and neck. In this context, PD-L1 protein expression has been proposed as a potentially valuable predictive marker. In the present study, expression of PD-L1 and PD-1 was evaluated by immunohistochemistry in 80 patients with predominantly HPV-negative oral squamous cell carcinomas and associated nodal metastasis. In addition, CD274/PD-L1 gene copy number status was assessed by fluorescence in situ hybridization analysis. PD-L1 expression was detected in 36/80 (45%) cases and concordance of PD-L1 expression in primary tumor and corresponding nodal metastasis was present in only 20/28 (72%) cases. PD-1 expression was found in tumor-infiltrating lymphocytes (TILs) but not in tumor cells. CD274/PD-L1 gene amplification was detected in 19% of cases, with high level PD-L1 amplification present in 12/80 (15%), and low level amplification in 3/80 (4%). Interestingly, CD274/PD-L1 gene amplification was associated with positive PD-L1 immunostaining in only 73% of cases. PD-L1 copy number status was concordant in primary tumor and associated metastases. Clinically, PD-L1 tumor immunopositivity was associated with a higher risk for nodal metastasis at diagnosis, overall tumor related death und recurrence. Based on our findings we propose to include PD-L1 copy number status in addition to protein status in screening programs for future clinical trials with immunotherapeutic strategies targeting the PD-1/PD-L1 axis.
| S-EPMC4914266 | biostudies-literature
Project description:BackgroundImmunotherapy using checkpoint inhibitors, especially PD-1/PD-L1 inhibitors, has now evolved into the most promising therapy for cancer patients. However, most of these inhibitors are monoclonal antibodies, and their large size may limit their tumor penetration, leading to suboptimal efficacy. As a result, there has been a growing interest in developing low-molecular-weight checkpoint inhibitors.MethodsWe developed a novel biopanning strategy to discover small peptide-based anti-PD-L1 inhibitors. The affinity and specificity of the peptides to PD-L1 were examined using various assays. Three-dimensional (3D) spheroid penetration study was performed to determine the tumor penetration capability of the peptides. Anti-tumor activity of the peptides was evaluated in mice bearing CT26 tumor cells.ResultsWe discover several anti-PD-L1 peptide inhibitors to block PD-1/PD-L1 interaction. The peptides exhibit high affinity and specificity to human PD-L1 protein as well as PD-L1-overexpressing human cancer cells MDA-MB-231 and DU-145. Molecular docking studies indicate that the peptide CLP002 specifically binds to PD-L1 at the residues where PD-L1 interacts with PD-1. The peptide also blocks the CD80/PD-L1 interaction, which may further enhance the immune response of tumor-infiltrating T cells. Compared to antibody, the peptide CLP002 exhibits better tumor penetration in a 3D tumor spheroid model. The peptide CLP002 restores proliferation and prevents apoptosis of T cells that are co-cultured with cancer cells. The peptide CLP002 also inhibits tumor growth and increases survival of CT26 tumor-bearing mice.ConclusionsThis study demonstrated the feasibility of using phage display to discover small peptide-based checkpoint inhibitors. Our results also suggested that the anti-PD-L1 peptide represents a promising low-molecular-weight checkpoint inhibitor for cancer immunotherapy.
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Project description:Programmed death-ligand 1 (PD-L1) and its receptor programmed cell death protein 1 (PD-1) modulate antitumor immunity and are major targets of checkpoint blockade immunotherapy. However, clinical trials of anti-PD-L1 and anti-PD-1 antibodies in breast cancer demonstrate only modest efficacy. Furthermore, specific PD-L1 contributions in various tissue and cell compartments to antitumor immunity remain incompletely elucidated. Here we show that PD-L1 expression is markedly elevated in mature adipocytes versus preadipocytes. Adipocyte PD-L1 prevents anti-PD-L1 antibody from activating important antitumor functions of CD8+ T cells in vitro. Adipocyte PD-L1 ablation obliterates, whereas forced preadipocyte PD-L1 expression confers, these inhibitory effects. Pharmacologic inhibition of adipogenesis selectively reduces PD-L1 expression in mouse adipose tissue and enhances the antitumor efficacy of anti-PD-L1 or anti-PD-1 antibodies in syngeneic mammary tumor models. Our findings provide a previously unappreciated approach to bolster anticancer immunotherapy efficacy and suggest a mechanism for the role of adipose tissue in breast cancer progression.
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Project description:Programmed cell death ligand-1 (PD-L1) detection assays have not been standardized for patients with colorectal cancer, and the prognostic value of PD-L1 expression is unclear. We compared the PD-L1 expression patterns in colorectal cancer samples using various immunohistochemical assays using 3 primary PD-L1 antibodies (assay 1, MIH1; assay 2, E1L3; and assay 3, 22C3) and investigated the prognostic implication of PD-L1 expression using each. Additionally, PD-L1 gene amplification was evaluated using FISH. The percentage scorings and positivity rates of the 3 assays differed; the degrees of correlation and concordance between assays 2 and 3 were relatively high, whereas assay 1 was an outlier. Multivariate analyses indicated that PD-L1 positivity in tumor cells and its negativity in tumor-infiltrating lymphocytes were independent predictors of poorer overall and disease-free survival in patients with colorectal cancer. PD-L1 gene amplification was found in 2 patients (PD-L1/CEP ratio, 5.60 and 5.84, respectively); both had strong PD-L1 expression according to immunohistochemistry. Overall, our study showed that PD-L1 expression status in tumor and immune cells is an independent prognostic factor in patients with colorectal cancer. Standardizations of both PD-L1 detection using immunohistochemistry and the cut-off for positivity are necessary. Finally, PD-L1 gene amplification was found in a small fraction of samples, suggesting the possibility of an ancillary test for PD-L1 evaluation.
| S-EPMC6125474 | biostudies-literature
Project description:Ovarian cancer (OC) is the most lethal gynecologic malignancy, affecting approximately 1 in 70 women with only 45% surviving 5 years after diagnosis. This disease typically presents at an advanced stage, and optimal debulking with platinum-based chemotherapy remains the cornerstone of management. Although most ovarian cancer patients will respond effectively to current management, 70% of them will eventually develop recurrence and novel therapeutic strategies are needed. There is a rationale for immune-oncological treatments (IO) in the managements of patients with OC. Many OC tumors demonstrate tumor infiltrating lymphocytes (TILs) and the degree of TIL infiltration is strongly and reproducibly correlated with survival. Unfortunately, results to date have been disappointing in relapsed OC. Trials have reported very modest single activity with various antibodies targeting PD-1 or PD-L1 resulting in response rate ranging from 4% to 15%. This may be due to the highly immunosuppressive TME of the disease, a low tumor mutational burden and low PD-L1 expression. There is an urgent need to improve our understanding of the immune microenvironment in OC in order to develop effective therapies. This review will discuss immune subpopulations in OC microenvironment, current immunotherapy modalities targeting these immune subsets and data from clinical trials testing IO treatments in OC and its combination with other therapeutic agents.
| S-EPMC8710491 | biostudies-literature
Project description:The CD274 (PD-L1)/PDCD1 (PD-1) pathway is crucial for the modulation of immune responses and self-tolerance. Aberrantly expressed CD274 allows tumor cells to evade host immune system and is considered to be a mechanism of adaptive immune resistance. Inhibition of the CD274/PDCD1 immune checkpoint offers a promising new therapeutic strategy. Although CD274-expressing tumor cells have been identified in different types of tumors including colorectal cancer, clinicopathologic profile of these CD274-positive tumors has not been extensively studied. In this study, 454 primary colorectal carcinomas were analyzed histologically and immunohistochemically for CD274, mismatch repair (MMR) proteins, intestinal differentiation marker (CDX2), and stem cell markers (ALCAM, ALDH1A1, and SALL4). CD274-positive colorectal carcinomas (54/454 (12%)) usually (83%) involved the right or transverse colon with poorly differentiated and solid/medullary histology. On the basis of multivariate logistic regression analysis, CD274 positivity was significantly associated with poorly differentiated histotype (OR: 3.32; 95% CI: 1.46-7.51; P=0.004), MMR deficiency (OR: 10.0; 95% CI: 4.66-21.5; P<0.001), and 'stem-like' immunophenotype defined by the loss or weak expression of CDX2 and ALCAM-positivity (OR: 5.51; 95% CI: 1.66-18.3; P=0.005). Mutation analysis of 66 arbitrary selected colorectal carcinomas revealed that CD274-positive tumors usually (88%) carried the BRAF V600E mutation. Thus, colorectal carcinomas defined by CD274 positivity displayed features associated with tumors arising via the serrated neoplasia pathway. Moreover, colorectal carcinomas characterized by lack of CDX2 and prominent expression of ALCAM frequently (71%) showed CD274 positivity. This might suggest association of CD274 expression with 'stem-like' phenotype. Further evaluation of a larger cohort or experimental analyses would be needed to confirm this notion.
| S-EPMC7900912 | biostudies-literature