The role of PD-L1 in the radiation response and clinical outcome for bladder cancer.
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ABSTRACT:
SUBMITTER: Wu CT
PROVIDER: S-EPMC4726250 | biostudies-other | 2016 Jan
REPOSITORIES: biostudies-other
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Project description:BackgroundThe activity of PD-1/PD-L1 inhibitors in the treatment of advanced bladder cancer (BC) is promising for many patients. However, a subset of patients do not benefit from treatment, thus leading to an effort to better identify predictive molecular biomarkers of response.ObjectiveTo conduct a systematic review of the literature on predictive molecular biomarkers associated with response to PD-1 and PD-L1 inhibitors in advanced bladder cancer, defined as locally-advanced, unresectable, or metastatic (mBC) disease.MethodsA search of the literature was performed using Embase (1947 - January 2019), Medline (1946 - January 2019), and EBM Reviews for Cochrane Central Register of Controlled Trials (as of December 2018). Studies examining the association of molecular biomarkers with clinical outcome in BC treated with PD-1 or PD-L1 monotherapy were included. Outcomes of interest were overall survival (OS), cancer-specific survival (CSS), progression-free survival (PFS), duration of response, and objective response rate (ORR).ResultsUsing the study search criteria, 899 unique abstract citations were found, of which 834 did not meet the eligibility criteria. Full text of the remaining 65 citations were screened, and 50 studies excluded, including 18 review articles. Eight additional studies from the bibliography of the review papers were included, making a total of 23 studies. Five PD-1 / PD-L1 antibodies have been tested in BC immunohistochemistry (IHC). These studies used different expression scoring criteria and generally had poor ability to discriminate likelihood for response. Overall, the data suggests CD8+ T cell infiltration is necessary to mediate an antitumor immune response, but other immune cell populations, such as neutrophils may suppress T cell-mediated immunity and efficacy of PD-1/PD-L1 blockade. An IFNγ signature is a promising predictor, but there needs to be consensus on the optimal gene panel composition, and prospective validation. Tumor mutation burden (TMB) is a promising predictor in six studies reporting on 1200 patients, but there is not a consensus on the optimal definition of "high TMB". Detection of T cell receptor (TCR) clonal expansion has only been conducted in small studies and so its predictive value remains inconclusive. Epithelial-mesenchymal transformation (EMT) and transforming growth factor β (TGFβ) are associated with poor prognosis and possibly intrinsic resistance to PD-1/PD-L1 checkpoint blockade, but more work needs to be done to build upon and confirm the initial findings.ConclusionsCurrently no molecular biomarker is sufficiently mature for routine clinical use, while some candidates, or a combination show great promise and need further study.
| S-EPMC7747768 | biostudies-literature
Project description:PurposeIn this study, we aimed to identify prognostic factors of cancer mortality in patients who received radical cystectomy and to identify genomic alterations in a sub-cohort of patients with locally advanced (pT3-4) and/or positive lymph nodes bladder cancer (BC).MethodsWe collected 101 BC samples from 2010 to 2018 who previously received radical cystectomy. Immunohistochemical slides were evaluated for PPAR, cAMP, IMP3, Ki67, CDK4, POU5F1, Cyclin E and MDM2, p65, CD3, CD4, CD8, CD20, CD68, CD163, FOXP3, PD-1 and PD-L1 expression. We calculated a prognostic score (PS) based on the positivity to PD-1, PD-L1 and of cAMP (final score ranging from 0 to 3). DNA of each sample have been used for sequencing by NGS in a sub-cohort of 6 patients with locally advanced (pT3-4) and/or positive lymph nodes BC.ResultsPD-1 + (HR [hazard ratio] 2.59; p = 0.04), PD-L1+ (HR = 6.46; p < 0.01) and cAMP+ (HR 3.04; p = 0.02) were independent predictors of cancer-specific mortality (CSM). Increase of PS (score = 0 as reference) was associated with CSM, 0.81 (p = 0.80), 4.72 (p = 0.01) and 10.51 (p < 0.0) for PS 1, 2 and 3, respectively. ERBB2 was the gene most frequently mutated.ConclusionBC exhibited heterogenous protein expression and variable genomic features. Identification of expression of PD-1, PD-L1 and cAMP could help in predicting oncological outcomes.
| S-EPMC10314864 | biostudies-literature
Project description:Platinum-based chemotherapy is the standard of care in metastatic bladder cancer. With the approval of various checkpoint inhibitors, immunotherapy has revolutionized the traditional treatment modalities. The aim of the study was to evaluate whether PD-L1 expression on tumor cells (TCs) and tumor-infiltrating immune cells (ICs) can be used as biomarker to predict recurrence-free survival (RFS), overall survival (OS) and disease-specific survival (DSS) in bladder cancer patients after radical cystectomy (RC) developing disease recurrence followed by first-line chemotherapy. PD-L1 was measured on formalin-fixed, paraffin-embedded tissue sections of RC specimens in all patients (n=61) and in 27 matched metastatic biopsy samples by immunohistochemistry. PD-L1 expression on TCs was defined by the percentage of PD-L1 positive tumor cells (< 1%= IC0, ≥1% but <5%=IC1, ≥5 %=IC2/3), and was considered negative or positive for ICs. On 27 paired samples, IC1/2/3 score on TCs was homogeneous distributed with 59.3% in primary tumors and metastases, but with a high discordance rate of 44.4% of PD-L1 positivity on ICs. High PD-L1 expression (IC2/3) on TCs was more frequently seen in histologic subtypes of urothelial cancer compared to pure urothelial cancers (46.2% vs. 20.8%; p=0.002). PD-L1 expression on TCs in primary tumors (IC2/3 vs. IC0, median: 3.2 vs. 13.8 months, p=0.019) and metastatic sites (IC2/3 vs. IC0, median: 6.1 vs. 21.8 months, p=0.014) was associated with poor chemo-response, represented by significant shortened DSS. These results suggest that PD-L1 may be a potential target being involved in chemo-resistance mechanisms and poses potential for therapy stratification in the future.
| S-EPMC5620140 | biostudies-literature
Project description:Several cancers are highly refractory to conventional chemotherapy. The survival of tumors in several cases is assisted by checkpoint immunomodulation to maintain the imbalance between immune surveillance and cancer cell proliferation. Check point antibody inhibitors, such as anti-PD-1/PD-L1, are a novel class of inhibitors that function as a tumor suppressing factor via modulation of immune cell-tumor cell interaction. These checkpoint blockers are rapidly becoming a highly promising cancer therapeutic approach that yields remarkable antitumor responses with limited side effects. In recent times, more than four check point antibody inhibitors have been commercialized for targeting PD-1, PDL-1, and CTLA-4. Despite the huge success and efficacy of the anti-PD therapy response, it is limited to specific types of cancers, which attributes to the insufficient and heterogeneous expression of PD-1 in the tumor microenvironment. Herein, we review the current landscape of the PD-1/PD-L1 mechanistic role in tumor immune evasion and therapeutic outcome for cancer treatment. We also review the current progress in clinical trials, combination of drug therapy with immunotherapy, safety, and future of check point inhibitors for multiple types of cancer.
| S-EPMC5572324 | biostudies-literature
Project description:BackgroundCyclin-dependent kinase 6 (CDK6) was proved to be an important regulator in the progression of cell cycle and has been a promising therapeutic target in cancer treatment. However, the clinical significance of CDK6 in muscle-invasive bladder cancer (MIBC) remains obscure. Herein, we attempt to explore the clinical relevance of CDK6 and assess the feasibility of the integrative model to predict immune checkpoint blockade (ICB) response.MethodsThis study enrolled 933 patients with muscle-invasive bladder cancer (MIBC) from Zhongshan Hospital (ZSHS), The Cancer Genome Atlas (TCGA), Chemo, IMvigor210 and UC-GENOME cohorts. Kaplan-Meier survival and Cox regression analyses were performed to assess clinical outcomes based on CDK6 expression.ResultsHigh CDK6 expression conferred poor prognosis and superior response to platinum-based chemotherapy but inferior response to ICB in MIBC. Furthermore, the integrative model named response score based on CDK6, PD-L1 and TMB could better predict the response to ICB and chemotherapy. Patients with higher response scores were characterised by inflamed immune microenvironment and genomic instability.ConclusionsCDK6 expression was correlated with prognosis and therapy response in MIBC. Integration of CDK6, PD-L1 and TMB could better identify patients who were most likely to benefit from ICB and chemotherapy.
| S-EPMC10912081 | biostudies-literature
Project description:ObjectiveImmunotherapy targeting the programmed cell death protein-1 (PD-1)/programmed cell death protein ligand 1 (PD-L1) pathway has been observed to be efficient in several solid tumors. We aim to investigate the prognostic significance of PD-1/PD-L1 expression profile in intrahepatic cholangiocarcinoma (ICC).Materials and methodsWe investigated the expression of PD-1, PD-L1, CD8+ T cells, and CD68+ macrophages in paired tumor and adjacent normal tissues from 322 ICC patients using tyramide signal amplification (TSA)-based multiplexed immunohistochemistry.ResultsWe found that high proportion of tumor-infiltrating CD8+ PD-1High within CD8+ PD-1+ T cells significantly correlated with advanced TNM stage (P = 0.035). ICC patients with high proportion of CD8+ PD-1High in CD8+ PD-1+ had worse postoperative survival than low proportion patients (P = 0.0037), which was an independently prognostic factor for OS (P = 0.025,). The density of CD68+ PD-L1+ significantly and positively correlated with the density of CD8+ PD-1High (P < 0.0001, r = 0.5927). The proportion of CD68+ PD-L1+ within CD68+ ICC was the risk factor for OS and TTR but not an independently factor for prognosis. The CD68+ PD-L1+ macrophages and CD8+ PD-1High T cells may cooperatively play a role in inhibiting anti-tumor immunity.ConclusionCD68+ PD-L1+ macrophages and CD8+ PD-1High T cells predict unfavorable prognosis, which could also bring new progress about immune target therapy in ICC research.
| S-EPMC7686719 | biostudies-literature
Project description:BackgroundTIGIT and PD-1 are checkpoint receptors that could regulate the functional status of immune cells through independent pathways. However, the clinical significance of immune classification based on TIGIT and PD-1 expression remains unclear in muscle-invasive bladder cancer (MIBC).MethodsPatients with MIBC from four independent cohorts were categorised into three clusters. Survival analysis conducted through Kaplan-Meier curves and Cox regression model. Immune contexture was measured by immunohistochemistry and CIBERSORT algorithm. Twenty-five fresh tumour tissue samples were utilised to evaluate functional state of CD8+ T cells by flow cytometry.ResultsCluster I (TIGITlowPD-1low) contained widely poor immune infiltrates with higher FGFR3 mutation, Cluster II (TIGITlowPD-1high) exhibited a highly infiltrated contexture with increased cytolytic CD8+ T cells and had the best prognosis, Cluster III (TIGIThigh) presented a suppressive tumour microenvironment (TME) featured by exhausted CD8+ T cells and basal molecular subtype. Patients of Cluster III had the worst survival but could benefit more from adjuvant chemotherapy and anti-PD-L1 immunotherapy, and also presented limited FGFR3 signalling signature but activated immunotherapeutic and EGFR-associated pathway.ConclusionsTIGIT/PD-1-based risk stratification with distinct immune and molecular features could be served as a predictor for systematic therapeutic response including adjuvant chemotherapy and immunotherapy in MIBC patients.
| S-EPMC9042924 | biostudies-literature
Project description:We have seen a notable increase in the application of PD-1/PD-L1 inhibitors for the treatment of several solid and hematogenous malignancies including metastatic melanoma, non-small-cell lung cancer and lymphoma to name a few. The need for biomarkers for identification of a suitable patient population for this type of therapy is now pressing. While specific biomarker assays have been developed for these checkpoint inhibitors based on their respective epitopes, the available studies suggested the clinical utility of these biomarker assays is for response stratification and not patient selection. Further improvement in assay development is needed to utilize this type of assay in identification of ideal patient population for this therapy.
| S-EPMC5353958 | biostudies-other
Project description:Background: Programmed death protein-1/ligand-1 (PD-1/L1) inhibitors have widely used in the treatment of lung cancer. Some literatures indicated that different gender might not have equal immune response, but no agreement have reached on the issue. Hence, we performed a systematic review and meta-analysis that examine the effect of gender on the clinical outcome of PD-1/PD-L1 inhibitor in advanced lung cancer patients. Methods: Related database and conferences were searched. Studies that reported the relationship between gender and the overall survival (OS) or progression-free survival (PFS) of PD-1/L1 inhibitor were included. Meta-analysis was conducted to obtain pooled hazard ratios (HRs) with 95% CI. Results: We included 34 studies with 11,883 lung cancer patients. Meta-analysis showed that PD-1/PD-L1 inhibitors significantly prolonged the OS (males: HR 0.71, 95%CI 0.66–0.77; females: HR 0.72, 95%CI 0.63–0.82) and PFS (males: HR 0.60, 95%CI 0.55–0.66; females: HR 0.72, 95%CI 0.62–0.84) versus chemotherapy. The clinical benefit (OS HR: 0.99; PFS HR: 0.83) was not statistically significant between males and females. In patients treated with cemiplimab, male patients had a better OS (0.53, 95%CI 0.42–0.66) and PFS (OS 1.51, 95%CI 0.80–2.82) compared with female patients, but the small number of female patients precludes us from drawing any firm conclusions in female subpopulations. Conclusion: The clinical benefit of PD-1/PD-L1 inhibitors was not statistically significant between males and females during the treatment of lung cancer. In the future, researchers who are designing new immunotherapy studies should ensure a larger inclusion of women in trials, to avoid erroneously extending to women results that are obtained mainly in male patients.
| S-EPMC10470728 | biostudies-literature
Project description:A large proportion of anti-tumor immunity research is focused on major histocompatibility complex class I (MHC-I) molecules and CD8+ T cells. Despite mounting evidence has shown that CD4+ T cells play a major role in anti-tumor immunity, the role of the MHC-II molecules in tumor immunotherapy has not been thoroughly researched and reported. In this study, we defined a MHC-II signature for the first time by calculating the enrichment score of MHC-II protein binding pathway with a single sample gene set enrichment analysis (ssGSEA) algorithm. To evaluate and validate the predictive value of the MHC class II (MHC-II) signature, we collected the transcriptome, mutation data and matched clinical data of bladder cancer patients from IMvigor210, The Cancer Genome Atlas (TCGA) databases and Gene Expression Omnibus (GEO) databases. Comprehensive analyses of immunome, transcriptome, metabolome, genome and drugome were performed in order to determine the association of MHC-II signature and tumor immunotherapy. We identified that MHC-II signature is an independent and favorable predictor of immune response and the prognosis of bladder cancer treated with immune checkpoint inhibitors (ICIs), one that may be superior to tumor mutation burden. MHC-II signature was significantly associated with increased immune cell infiltration and levels of immune-related gene expression signatures. Additionally, transcriptomic analysis showed immune activation in the high-MHC-II signature subgroup, whereas it showed fatty acid metabolism and glucuronidation in the low-MHC-II signature subgroup. Moreover, exploration of corresponding genomic profiles highlighted the significance of tumor protein p53 (TP53) and fibroblast growth factor receptor 3 (FGFR3) alterations. Our results also allowed for the identification of candidate compounds for combined immunotherapy treatment that may be beneficial for patients with bladder cancer and a high MHC-II signature. In conclusion, this study provides a new perspective on MHC-II signature, as an independent and favorable predictor of immune response and prognosis of bladder cancer treated with ICIs.
| S-EPMC8873787 | biostudies-literature