Programmed Death-ligand 1 Positivity Research Articles

Prognostic value of PD-L1 combined positive score in patients with upper tract urothelial carcinoma.

Upper tract urothelial carcinoma (UTUC) is relatively rare in Western countries. The impact of programmed death-ligand 1 (PD-L1) expression on UTUC remains unclear because previous studies have focused on bladder UC. We investigated the association of PD-L1 expression with clinicopathological features and prognosis in patients with UTUC. We retrospectively reviewed the patients with UTUC that we treated at our institute from 2013 to 2018. In total, 105 patients with UTUC undergoing radical nephroureterectomy were analyzed to evaluate the PD-L1 expression on representative whole-tissue sections using the Combined Positive Score (CPS; Dako 22C3 pharmDx assay). A PD-L1 CPS ≥ 10 was considered positive. Among the 105 UTUC cases, 17.1% exhibited positive PD-L1 expression. A CPS ≥ 10 was significantly associated with higher tumor stage (≥ T2, p = 0.034) and lymph node invasion at diagnosis (p = 0.021). A multivariable analysis indicated that a CPS ≥ 10 was an independent prognostic predictor of shorter cancer-specific survival (hazard ratio [HR] = 4.59, 95% confidence interval [CI] = 1.66 - 12.7, p = 0.003) and overall survival (HR = 2.51, 95% CI = 1.19 - 5.27, p = 0.015). A PD-L1 CPS ≥ 10 in UTUC was associated with adverse pathological features and independently predicted worse cancer-specific and overall survival.

Programmed Death Ligand 1 Expression as a Prognostic Marker in Patients with Advanced Biliary Tract Cancer

Background: Biliary tract cancer (BTC) is associated with poor prognosis because of its aggressive and heterogeneous nature. Programmed death ligand 1 (PD-L1) has been considered a novel biomarker for prognosis and response of immune checkpoint inhibitors in various tumors. However, there are limited data reporting on the role of PD-L1 in advanced BTC patients. Patients and Methods: We analyzed 186 patients with advanced BTC who received palliative gemcitabine and platinum between May 2010 and December 2019. All patients were evaluated for PD-L1 expression by combined positive score positivity. Results: Of the 186 patients, the primary tumor location was intrahepatic cholangiocarcinoma (IHCC) in 72 (38.7%), extrahepatic cholangiocarcinoma (EHCC) in 90 (48.4%), and gallbladder (GB) cancer in 24 (12.9%). Among all the patients, 53 (28.5%) had PD-L1 positivity. The median overall survival (OS) of patients with PD-L1 positivity or negativity was 12.1 and 15.4 months, respectively. The median progression-free survival (PFS) in patients with PD-L1 positivity or negativity was 5.7 and 7.1 months, respectively. OS and PFS were not statistically different between groups. In subgroup analysis, EHCC patients with PD-L1 negativity had more favorable OS (17.2 vs. 11.6 months, p = 0.002) and PFS (7.8 vs. 5.4 months, p = 0.005) than those who were PD-L1-positive. However, this finding was not reproduced in patients with IHCC or GB cancer. Conclusion: This study demonstrated that PD-L1 expression might be a novel prognostic biomarker in patients with EHCC but not in patients with IHCC or GB cancer.

Prognostic significance of PD-L1-positive cancer-associated fibroblasts in patients with triple-negative breast cancer

BackgroundCancer-associated fibroblasts (CAFs) are some of the most abundant components of the tumour microenvironment. A recent study suggested that in some cancers, CAFs express programmed death ligand 1 (PD-L1), which can act as a prognostic marker. The aim of this study was to investigate the clinicopathological significance of CAF PD-L1 expression in patients with triple-negative breast cancer (TNBC) and to identify the most suitable primary antibody for immunostaining for CAF PD-L1.MethodsImmunohistochemical staining (primary antibodies of 73–10, SP142, and E1L3N) and tissue microarrays were used to analyse the expression profiles of PD-L1 in CAF in 61 patients with TNBC who underwent surgery. Overall survival (OS) was compared based on CAF PD-L1 expression, and the risk factors for OS were analysed. The relationship between clinicopathological parameters and survival was also examined.ResultsThirty-four (55.7%) patients were positive for CAF PD-L1 (73–10) expression. Compared with CAF PD-L1 negativity, there was a significant correlation between CAF PD-L1 positivity and better OS (p = 0.029). CAF PD-L1 expression, evaluated using SP-142 or E1L3N, did not correlate with OS. CAF PD-L1-positivity (73–10) correlated significantly with better prognosis in multivariate analyses (hazard ratio: 0.198; 95% confidence interval: 0.044–0.891; p = 0.035).ConclusionsCAF PD-L1 expression is a novel marker for a better prognosis of patients with TNBC, and the 73–10 assay may be suitable for immunostaining CAF PD-L1.

Anti-PD-1 Monotherapy for Advanced NSCLC Patients with Older Age or Those with Poor Performance Status.

PurposeAnti-programmed death 1 (PD-1) antibodies have emerged as frontline treatments for patients with advanced non-small cell lung cancer (NSCLC) on the basis of global Phase III trials. However, current data regarding responses to anti–PD-1 therapy in older patients with NSCLC or those with poor performance status (PS) are limited. Therefore, we examined the therapeutic effect of anti PD-1 antibody in these patients.PatientsWe retrospectively examined consecutive patients treated with anti–PD-1 monotherapy (pembrolizumab or nivolumab) from January 2016 to September 2018.ResultsWe enrolled 125 patients (median age, 60 years), 80.8% of whom were men. Patients aged ≥75 years were considered older patients (n = 15), and those with PS 2–3 were regarded as having poor PS (n = 11). The objective response and disease control rates were 15.4% and 46.2%, respectively, in older patients and 9.1% and 27.3%, respectively, in those with poor PS. Progression-free survival (PFS) and overall survival (OS) did not significantly differ between older and younger patients. However, poor PS was significantly associated with poor survival. High programmed death ligand 1 (PD-L1) expression in tumor specimens (≥50%) was associated with favorable survival in the entire cohort as well as patients with poor PS. Safety analyses demonstrated no significant difference in the occurrence of any adverse event, including grade ≥3 adverse events, between patients with poor PS or older age and the remaining patients.ConclusionAnti–PD-1 therapy had similar efficacy in older and younger patients with NSCLC, whereas survival was significantly worse in patients with poor PS. However, immune checkpoint inhibitors may be considered for patients with poor PS harboring positive PD-L1 expression.

A Real-world Study on the Assessment of Pathological Characteristics and Targeted Therapeutic Effect of Non-small Cell Lung Cancer Patients with Positive Driving Genes and High PD-L1 Expression

背景与目的驱动基因突变阳性患者行靶向治疗，驱动基因阴性但程序性死亡配体1（programmed death-ligand 1, PD-L1）高表达患者行免疫抑制剂治疗，是晚期非小细胞肺癌（non-small cell lung cancer, NSCLC）患者一线治疗的首选，但对于驱动基因阳性且PD-L1高表达患者的治疗选择仍值得探究。方法以315例NSCLC患者为研究对象，分析驱动基因阳性且PD-L1高表达患者的临床病理特征及靶向治疗疗效。结果本研究纳入的315例NSCLC患者中，驱动基因突变总阳性率为62.2%，PD-L1高表达率（≥50.0%）为11.2%，驱动基因阳性且PD-L1高表达的患者比例为10.7%。其中表皮生长因子受体（epidermal growth factor receptor, EGFR）突变、KRAS 突变、ALK融合、BRAF突变和MET 14外显子跳跃突变患者中均有PD-L1高表达，比例分别为7.8%（11/141）、18.2%（4/22）、23.1%（3/13）、50.0%（2/4）和100.0%（1/1）。EGFR突变且PD-L1高表达患者主要为Ⅳ期肺腺癌患者，KRAS突变且PD-L1高表达患者主要为有吸烟史的患者。其中详细跟踪了两例分别为ALK融合阳性且PD-L1高表达（90.0%）和EGFR L858R突变且PD-L1高表达（70.0%）患者的靶向治疗全过程，两例患者总生存期分别仅为5个月和2个月。结论NSCLC患者各驱动基因突变与PD-L1高表达共存的比例和临床病理特征有较大差异。发生敏感突变且PD-L1高表达的患者靶向治疗疗效和预后可能更差。

CMTM6 expression as a potential biomarker for immunotherapy in metastatic renal cell carcinoma.

The introduction of immune checkpoint inhibitors (ICIs) has revolutionized the treatment of metastatic renal cell carcinoma (mRCC) [1]. The expression of programmed death-ligand 1 (PD-L1) as assessed by immunohistochemistry (IHC) has been extensively studied as predictive biomarker for patients receiving ICIs. However, results in clinical RCC trials concerning the predictive value of PD-L1 expression were highly controversial [2]. In the Checkmate 214 trial [3], patients with PD-L1 positivity were found to benefit most from ICI combination. On the contrary, PD-L1 expression was not found to be predictive for nivolumab in the 2nd line setting [4]. Thus, all ICIs (combination and monotherapy) were approved in mRCC, irrespective of PD-L1 status.

Prognostic Value of Programmed Death Ligand-1 Expression on Tumor-Infiltrating Immune Cells in Patients Treated with Cisplatin-Based Combination Adjuvant Chemotherapy Following Radical Cystectomy for Muscle-Invasive Bladder Cancer: A Retrospective Cohort Study.

PurposeTo investigate the prognostic value of programmed death ligand-1 (PD-L1) expression in tumor-infiltrating immune cells (ICs) in men treated with adjuvant chemotherapy (AC) following radical cystectomy (RC) for muscle-invasive bladder cancer (MIBC).Materials and MethodsWe retrospectively reviewed 219 “high-risk” (≥pT3a and/or pN+) patients who underwent RC and received cisplatin-based AC for MIBC between March 2015 and September 2019. PD-L1 expression was measured using the VENTANA (SP-142) immunohistochemistry assay and categorized into the three groups according to the percentage of the tumor area covered by PD-L1 expression on ICs: IC0 (<1%), IC1 (≥1% and <5%), and IC2/3 (≥5%). Positive PD-L1 expression was defined as IC2/3 (≥5%). Kaplan–Meier survival analysis was used to assess recurrence-free survival (RFS), and Cox proportional hazard models were applied to identify factors predicting tumor recurrence.ResultsIn the entire cohort, the overall prevalence of PD-L1 IC0, IC1, and IC2/3 was 13.2%, 27.4%, and 59.4%, respectively. During the mean follow-up of 32.5 months, tumor recurrence was detected in 115 (52.5%) patients. On multivariable analysis, tumor stage (≥pT3; P=0.032), positive lymph nodes (P=0.001), and positive PD-L1 on ICs (P=0.005) were independent predictors of tumor recurrence. The 3 year RFS was 54.7% in patients with negative PD-L1 and 31.7% in patients with positive PD-L1.ConclusionPD-L1 is widely expressed in ICs. Positive PD-L1 on ICs was significantly associated with shorter RFS in patients treated with cisplatin-based AC following RC. The present results support the use of adjuvant immunotherapy in “high-risk” patients with PD-L1-expressing ICs.

CMTM6 and PD-L1 coexpression is associated with an active immune microenvironment and a favorable prognosis in colorectal cancer

BackgroundCKLF-like MARVEL transmembrane domain-containing 6 (CMTM6), a programmed death-ligand 1 (PD-L1) regulator, is widely expressed in various tumors and regulates the immune microenvironment. However, its prognostic value remains controversial, and...

Potential of circulating immune cells as biomarkers of nivolumab treatment efficacy for advanced hepatocellular carcinoma

Remarkable progress has been made in immunotherapy, specifically antibodies for programmed death 1 (PD-1) or programmed death-ligand 1 (PD-L1), for treating advanced cancers. In this study, we explored whether circulating immune cells can be used as biomarkers of the efficacy of such therapy. We enrolled patients who received nivolumab, an anti-PD-1 antibody, for advanced hepatocellular carcinoma (HCC) in clinical trials and who consented to the collection of their peripheral blood. Using flow cytometry, we analyzed lymphocyte subclasses and the PD-1 or PD-L1 positivity of immune cells. These results were compared between patients with disease control (complete response, partial response, or stable disease) and those with disease progression. This study included 16 patients. The objective response rate was 19%, and the disease control rate was 75%. The hemogram results and the percentage of total αβ T cells or CD4 T cells did not significantly change after nivolumab treatment; moreover, they were not associated with treatment outcomes. The number of CD8 T cells significantly increased after 4 weeks (p = 0.016); however, this change was not associated with treatment outcomes. Patients with disease control exhibited peripheral B cells with significantly lower pretreatment PD-1 positivity than did patients with disease progression (p = 0.042). Patients with disease progression were more likely to exhibit monocytes with increased PD-L1 positivity after 28 (p = 0.020) or 42 (p = 0.008) days of treatment. The low pretreatment PD-1 positivity of peripheral B cells and the constant posttreatment PD-L1 positivity of monocytes were associated with disease control after nivolumab treatment for advanced HCC.

The role of clinical factors and immunocheckpoint molecules in the prognosis of patients with supratentorial extraventricular ependymoma: a single-center retrospective study

PurposeSupratentorial extraventricular ependymoma (SEE) is a rare subset of ependymomas located in the supratentorial parenchyma, and little is known regarding its management and prognosis. Our study aimed to reveal the prognostic factors in patients with SEE and the roles of programmed death ligand-1 (PD-L1), programmed cell death protein 1 (PD-1), Ki-67, and neural cell adhesion molecule L1 (L1CAM) in predicting these patients’ outcomes.MethodsWe retrospectively studied the clinical features and prognostic factors in 48 patients with SEE admitted to our center from April 2008 to October 2018. Tissue slides were constructed from patient samples, and PD-L1, PD-1, Ki-67, and L1CAM expression levels were evaluated by immunohistochemistry.ResultsPatients with gross total resection (GTR) had better progression-free survival than patients with subtotal resection (STR). Moreover, the recurrence hazard ratios in patients with STR at 3, 5, and 10 years were 8.746, 6.866 and 3.962 times those of patients with GTR, respectively. PD-L1 positivity predicted worse progression-free survival, while the recurrence hazard ratios for patients with PD-L1 positivity at 3, 5, and 10 years were 10.445, 5.539, and 3.949 times those of patients with PD-L1 negativity, respectively. Multivariate analysis revealed that PD-L1 expression and GTR could independently predict outcomes in patients with SEE.ConclusionPD-L1 expression was an independent and more readily obtained predictor of outcomes, representing a simple and reliable biological prognostic factor for patients with SEE. Further studies are needed to explore PD-L1 inhibitor treatment for patients with ependymoma.Clinical trial registrationNo clinical trials were performed in the study.

Prognostic and Predictive Role of Neutrophil to lymphocyte Ratio in Second Line Immunotherapy of Non-small Cell Lung Cancer

<i>Background</i>: Programmed death-ligand 1 (PD-L1) expression at immunohistochemistry is the only approved, but still unsatisfactory, biomarker for immunotherapy in Non-Small Cell Lung Cancer (NSCLC). Neutrophil to Lymphocyte ratio (NLR) is a surrogate of systemic inflammation and could correlate with outcome to immunotherapy. This retrospective study (NCT03816657) explored the role of NLR in predicting benefit to nivolumab and susceptibility to hyperprogression (HPD). <i>Methods</i>: PD-L1, baseline and on-therapy NLR values were available in 173NSCLC patients receiving nivolumab. PD-L1 positivity was defined as expression on ≥1% of tumor cells; NLR was dichotomized in high (≥5) or low (<5). Patients were divided in 4 cohorts: 1 (PD-L1+/low NLR), 2 (PD-L1-/high NLR), 3 (PD-L1+/high NLR), 4 (PD-L1-/low NLR). A landmark analysis explored the impact of cohorts and NLR change on objective response rate (ORR), progression-free survival (PFS), overall survival (OS) and its influence on HPD. <i>Results</i>: PD-L1 was positive in 48% and negative in 52% of cases. Pre-treatment NLR was ≥5in 42% and <5 in 58%of patients; on-treatment NLR was ≥5in approximately 50% of patients. PD-L1 positivity was not associated with outcome. Both high pre- and on-therapy NLR was a negative predictor of ORR (p=0.004), PFS (p<0.0001) and OS (p<0.0001). High NLR cohorts (2 and 4) showed poorer outcome than low NLR cohorts. Relative NLR excursion ≥25% at 4 weeks from nivolumab start was associated with reduced PFS and OS, while its decrease or stability was associated with improved outcomes. Although NLR value and its dynamic did not influence HPD occurrence (p=0.062), 53% of hyperprogressors belonged to high NLR cohorts. <i>Conclusion</i>: The current retrospective analysis supports the role of high NLR as a independent negative predictive factor. Its increment during immunotherapy may identify patients with low likelihood of response to immunotherapy.

The clinicopathological significance and predictive value for immunotherapy of programmed death ligand-1 expression in Epstein-Barr virus-associated gastric cancer

ABSTRACT The effect of anti-programmed cell death 1 (PD-1) antibody in Epstein-Barr virus-associated gastric cancer (EBVaGC) was debatable, and no predictive biomarkers for efficacy have been reported. Public reports on anti-PD-1 antibody monotherapy-treated EBVaGC with available programmed death ligand-1 (PD-L1) expression status were summarized and analyzed. Relevance with clinicopathologic characteristics of PD-L1 expression by immunohistochemistry was analyzed in 159 patients diagnosed with EBVaGC. Relevance with genomic transcriptome and mutation profile of PD-L1 status in EBVaGC was assessed with three datasets, the cancer genome atlas (TCGA), Gene Expression Omnibus (GEO) GSE51575, and GSE62254. Based on the data from 8 reports, patients with positive PD-L1 expression (n = 30) had significantly superior objective response rate (ORR) than patients with negative PD-L1 expression (n = 9) (63.3% vs. 0%, P = .001) in EBVaGC receiving anti-PD-1 antibody monotherapy. PD-L1 positivity was associated with less aggressive clinicopathological characteristics and was an independent predictor for a longer disease-free survival (hazard ratio [HR] and 95% CI: 0.45 [0.22–0.92], P = .03) and overall survival (HR and 95% CI: 0.17 [0.06–0.43], P < .001). Analysis of public EBVaGC transcriptome and mutation datasets revealed enhanced immune-related signal pathways in PD-L1high EBVaGC and distinct mutation patterns in PD-L1low EBVaGC. PD-L1 positivity indicates a subtype of EBVaGC with ‘hot’ immune microenvironment, lower aggressiveness, better prognosis, and higher sensitivity to anti-PD-1 immunotherapy.

PD-L1 Expression in Medullary Thyroid Carcinoma and Its Association with Clinicopathological Findings.

< strong > Objective: < /strong > Medullary thyroid carcinoma (MTC) is a rare tumor originating from parafollicular C cells. It has more aggressive biologic behavior than differentiated thyroid carcinomas, and it is insensitive to treatment with radioactive iodine. Vandetanib and cabozantinib are the newly approved tyrosine kinase inhibitors in advanced stages, but novel effective systemic therapeutics could be crucial and needed for the clinical management of these patients. We aimed to evaluate the Programmed death-ligand 1 (PD-L1) expression, which is a novel immunotherapy target, in our MTC cohort, and determine whether it has an association with clinical and pathological features. < strong > Material and Method: < /strong > This retrospective study involved 41 cases of MTC with a median follow-up of 54 months. PD-L1 monoclonal antibody (SP263 clone) was investigated immunohistochemically. Complete and/or partial membranous staining pattern in more than 1% of tumor cells was considered positive. The correlations of PD-L1 expression with clinicopathologic and prognostic features were analyzed. < strong > Results: < /strong > PD-L1 positivity was detected in 5 (12.2%) of 41 tumors. The extent of PD-L1 staining was low ( < 5%) for all tumors. There was no clinicopathologic and prognostic relevance regarding PD-L1 expression in our MTC patients. < strong > Conclusion: < /strong > Although PD-L1 expression could be a potential biomarker to predict the prognosis of various cancers and response to checkpoint inhibitors, we did not find any significant correlation between PD-L1 expression and clinicopathologic features in our cases. Studies with larger patient numbers are still required to perform a more comprehensive analysis.

Systematic review and meta-analysis of PD-L1 expression discordance between primary tumor and lung cancer brain metastasis.

BackgroundNovel immunotherapeutic strategies targeting the programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) axis are often administered when metastatic tumors show PD-L1 positivity, even in the setting of lung cancer brain metastasis (LCBM). However, biological differences exist between primary tumors and metastatic sites. The objective of this study was to analyze rates of PD-L1 receptor discordance between primary tumors and LCBM.MethodsA systematic review of studies of biopsied or resected LCBM evaluating PD-L1 discordance published in the Medline database was performed using PRISMA guidelines. Weighted random effects models were used to calculate pooled estimates.ResultsSix full-text articles (n = 230 patients) with a median of 32 patients in each study (range: 24–73) reported PD-L1 receptor expression analyses of both primary lung tumors and brain metastases and met inclusion criteria. The pooled estimate for tumor cell (TC) PD-L1 receptor discordance between primary tumors and LCBM was 19% (95% confidence interval [CI]: 10–27%). For PD-L1 receptor expression in tumor-infiltrating lymphocytes (TIL), the weighted pooled estimate for discordance was 21% (95% CI: 8–44%). For primary versus LCBM, the positive rates by expression levels of <1%, 1–50%, and >50% were 52% (95% CI: 30–73%) versus 56% (95% CI: 34–76%), 30% (95% CI: 22–40%) versus 20% (95% CI: 10–35%), and 15% (95% CI: 6–36%) versus 22% (95% CI: 15–31%) (P = .425), respectively.ConclusionsPD-L1 discordance occurs in ~20% of LCBM, with the greatest discordance in the 1–50% expression category. Although controversial, confirming discordance might be important for selection of immune checkpoint inhibitor therapy and in the analysis of patterns of failure after treatment.

Combining PD-L1 Expression and Standardized Uptake Values in FDG-PET/CT Can Predict Prognosis in Patients With Resectable Non-Small-Cell Lung Cancer.

BackgroundThis study aimed to determine the relationship of programmed death-ligand 1 (PD-L1) expression and standardized uptake values in fluorodeoxyglucose–positron emission tomography/computed tomography (FDG-PET/CT) with prognosis in non–small-cell lung cancer (NSCLC).MethodsWe retrospectively analyzed 328 NSCLC patients who underwent lobectomy/segmentectomy with lymph node dissection. PD-L1 expression was detected by immunohistochemically stained using the murine monoclonal antibody clone 22C3. The preoperative maximum standardized uptake value (SUVmax) of FDG-PET/CT at the primary lesion; pathological factors including histological type, microscopic lymphatic, venous, and pleural invasion; and lymph node metastases in resected specimens was determined. Significant prognostic clinicopathologic factors were analyzed by univariate and multivariate analyses.ResultsPD-L1 expression was higher in men, smokers, squamous cell carcinoma, advanced pathologic stages, positive venous invasion, positive pleural invasion, and high preoperative SUVmax (≥3). Postoperative survival analysis showed that both PD-L1 expression and preoperative SUVmax were significantly negative prognostic factors in univariate analysis for overall survival (OS) (P = 0.0123 and P < 0.0001) and relapse-free survival (RFS) (P = 0.0012 and P < 0.0001). Kaplan–Meier survival curves showed that the OS and RFS were the best in patients with negative PD-L1 expression and SUVmax < 3, intermediate in patients with positive PD-L1 expression and SUVmax < 3 and those with negative PD-L1 expression and SUVmax ≥ 3, and poor in patients with positive PD-L1 expression and SUVmax ≥ 3.ConclusionCombining PD-L1 expression and preoperative FDG-PET/CT SUVmax in primary tumor might help in accurate prediction of postoperative prognosis in NSCLC patients.

Assessment of PD-L1 expression in patients with neuroblastoma and renal tumors.

Programmed death 1 (PD-1) is a co-receptor which is located at the surface of cells like natural killer, monocytes, T and B cells. It has two ligands including programmed death ligand-1 (PD-L1) and ligand-2 (PD-L2). T cell functions are inhibited by activation of PD-1/PD-L1 pathway and this pathway is used by viruses and some tumor cells in order to escape from immune eradication. In our study we evaluated PD-L1 expression in the tissue specimens of patients with Wilms tumor, neuroblastoma and other renal tumors. Totally 60 patients who were followed up at Gazi University Hospital with the diagnosis of neuroblastoma, Wilms tumor and other renal tumors were included. PD-L1 expression was examined in tumor samples of the patients. Positive staining with PD-L1 was detected only in two male patients. Both of them had neuroblastoma and advanced stage disease. None of the patients with Wilms tumor and other renal tumors had positive PD-L1 staining. Unlike adult tumors, PD-L1 expression is not common in childhood tumors due to differences in immune system between children and adults. Further studies are needed to establish the importance and effects of PD-1/PD-L1 pathway in pediatric tumors.

ARID1A Deficiency Is Associated With High Programmed Death Ligand 1 Expression in Hepatocellular Carcinoma.

The clinicopathological features of carcinomas expressing AT‐rich interaction domain 1a (ARID1A) and programmed death ligand 1 (PD‐L1) in HCC are poorly understood. Here, we examined ARID1A and PD‐L1 expression in surgically resected primary hepatocellular carcinoma (HCC) and the association of ARID1A and PD‐L1 expression with clinicopathological features and patient outcomes. Their association with ARID1A expression and tumor‐associated CD68‐positive macrophage was further explored. Using a database of 255 patients who underwent hepatic resection for HCC, immunohistochemical staining of ARID1A, PD‐L1, and CD68 was performed. We also analyzed the expression PD‐L1 after ARID1A knockdown in HCC cell lines. Samples from 81 patients (31.7%) were negative for ARID1A. Negative ARID1A expression was significantly associated with male sex, high alpha‐fetoprotein, high des‐gamma‐carboxyprothrombin, large tumor size, high rate of poor differentiation, microscopic intrahepatic metastasis, and PD‐L1 expression. In addition, negative ARID1A expression was an independent predictor for recurrence‐free survival, overall survival, and positive PD‐L1 expression. Stratification based on ARID1A and PD‐L1 expression in cancer cells was also significantly associated with unfavorable outcomes. PD‐L1 protein expression levels were increased through phosphoinositide 3‐kinase/AKT signaling after ARID1A knockdown in HCC cells. HCC with ARID1A‐low expression was significantly correlated with high levels of tumor‐associated CD68‐positive macrophage. Conclusion: Our large cohort study showed that ARID1A expression in cancer cells was associated with a poor clinical outcome in patients with HCC, PD‐L1 expression in cancer cells, and tumor microenvironment. Therefore, ARID1A may be a potential molecular biomarker for the selection of patients with HCC for anti‐programmed death 1/PD‐L1 antibody therapy.

PD-L1 Expression in Normal Endocrine Tissues Is Not Increased Despite High Incidence of PD-1 Inhibitor-Associated Endocrinopathies

ObjectiveTreatment with immune-checkpoint inhibitors often results in endocrine immune-related adverse events (irAEs), affecting the pituitary, thyroid, adrenal, and parathyroid glands and pancreas. The mechanism underlying the endocrine irAEs has not been fully elucidated, and it remains unclear why endocrine organs are so commonly affected. In the present study, we evaluated immunostaining patterns of programmed death-ligand 1 (PD-L1) in normal endocrine tissues to determine whether increased expression may explain the predilection of endocrinopathies in patients treated with programmed cell death-1 inhibitors. MethodsNormal formalin-fixed paraffin-embedded endocrine tissues (pituitary, thyroid, adrenal, pancreas, and parathyroid) were collected from our hospital’s pathology tissue archive. The tissues were assessed for membranous and cytoplasmic PD-L1 immunostaining using the Dako 22C3 pharmDx assay on an automated staining platform. ResultsWe examined 49 endocrine tissues, including 12 thyroid, 5 pancreatic, 17 adrenal, 5 parathyroid, and 10 pituitary samples. Samples with less than 1% membranous PD-L1–positive cells were considered negative, while those with more than 1% of PD-L1 membranous staining were considered positive. Immunostaining result of immune-related cells was also evaluated, considering the cytoplasmic PD-L1–positive cells with the same cutoff of 1%. None of the endocrine tissues demonstrated PD-L1 positivity higher than 1% in the relevant cells. ConclusionWhile our results do not suggest a role of PD-L1 expression in the pathogenesis of endocrine irAEs, they may serve as a basis for future studies further investigating the mechanisms of autoimmune, inflammatory, or malignant endocrine conditions.

Comprehensive Genomic Profiling of Carcinoma of Unknown Primary Origin: Retrospective Molecular Classification Considering the CUPISCO Study Design.

BackgroundCarcinoma of unknown primary origin (CUP) accounts for 2%–5% of newly diagnosed advanced malignancies, with chemotherapy as the standard of care. CUPISCO (NCT03498521) is an ongoing randomized trial using comprehensive genomic profiling (CGP) to assign patients with CUP to targeted or immunotherapy treatment arms based on genomic profiling. We performed a retrospective analysis of CUP cases referred for CGP to determine how many were potentially eligible for enrollment into an experimental CUPISCO arm.Materials and MethodsCentrally reviewed adenocarcinoma and undifferentiated CUP specimens in the FoundationCore database were analyzed using the hybrid capture‐based FoundationOne CDx assay (mean coverage, >600×). Presence of genomic alterations, microsatellite instability (MSI), tumor mutational burden (TMB), genomic loss of heterozygosity (gLOH), and programmed death‐ligand 1 (PD‐L1) positivity were determined.ResultsA total of 96 of 303 patients (31.7%) could be matched to an experimental CUPISCO arm. Key genomic alterations included ERBB2 (7.3%), PIK3CA (6.3%), NF1 (5.6%), NF2 (4.6%), BRAF (4.3%), IDH1 (3.3%), PTEN, FGFR2, EGFR (3.6% each), MET (4.3%), CDK6 (3.0%), FBXW7, CDK4 (2.3% each), IDH2, RET, ROS1, NTRK (1.0% each), and ALK (0.7%). Median TMB was 3.75 mutations per megabase of DNA; 34 patients (11.6%) had a TMB ≥16 mutations per megabase. Three patients (1%) had high MSI, and 42 (14%) displayed high PD‐L1 expression (tumor proportion score ≥50%). gLOH could be assessed in 199 of 303 specimens; 19.6% had a score of >16%.ConclusionsThirty‐two percent of patients would have been eligible for targeted therapy in CUPISCO. Future studies, including additional biomarkers such as PD‐L1 positivity and gLOH, may identify a greater proportion potentially benefiting from CGP‐informed treatment. Clinical trial identification number. NCT03498521Implications for PracticeThe findings of this retrospective analysis of carcinoma of unknown primary origin (CUP) cases validate the experimental treatment arms being used in the CUPISCO study (NCT03498521), an ongoing randomized trial using comprehensive genomic profiling to assign patients with CUP to targeted or immunotherapy treatment arms based on the presence of pathogenic genomic alterations. The findings also suggest that future studies including additional biomarkers and treatment arms, such as programmed death‐ligand 1 positivity and genomic loss of heterozygosity, may identify a greater proportion of patients with CUP potentially benefiting from comprehensive genomic profiling‐informed treatment.

PD-L1 expression in immune cells is a favorable prognostic factor for nasopharyngeal carcinoma.

Programmed death-ligand 1 (PD-L1) has been determined as a reliable prognostic factor for various malignancies. In this study, we aimed to determine the prognostic effect of PD-L1 expression in tumor-infiltrating immune cells (TIICs) of nasopharyngeal carcinoma (NPC) patients. Seventy patients diagnosed with non-metastatic NPC were included in the study. PD-L1 expression on immune cells was analyzed by immunohistochemical method. Patients were categorized into two groups according to the PD-L1 expression level in TIICs (level of PD-L1 staining ≥5% positive vs <5% negative). Median follow-up period was 34 months (range = 1 - 188). 1 and 2 years survival rate were found as 75% and 63% in PD-L1 negative TIICs group (47%), and 85% and 83% in PD-L1 positive TIICs group (53%), respectively. PD-L1 positivity in immune cells (ICs) was detected in 53% of the patients. The survival rate was found better in the PD- L1 positive group compared to the negative group (P = 0.049). In conclusion, the survival rate was found significantly better in the PD-L1 positive TIICs group, compared to the negative group.