Prognostic Significance Of PD-L1 Expression Research Articles

Prognostic importance of PD-L1 expression in bladder cancer patients.

PD-L1/PD-1 molecules are known as important mediators in immune-escape mechanisms of tumors. PD-L1 is highly expressed in various malignancies, including bladder cancer. However, the prognostic value of PD-L1 in bladder cancer patients remains controversial. To investigate the prognostic significance of PD-L1 expression in tumor tissues of bladder cancer patients. RNA was isolated from FFPE tumor tissues of 48 bladder cancer patients using the monophasic phenol and guanidine isothiocyanate method. Total RNA was converted to cDNA and gene expression levels were analyzed by qRT-PCR. The differential expression levels of the PD-L1 gene between tumor grade and cancer stage groups were analyzed by independent student's t-test and one-way ANOVA. Statistically significantly increased PD-L1 expression was observed in the high-grade tumor group (p < 0.05). No significant difference in PD-L1 expression was found among pTa, pT1, and pT2 groups. In addition, the difference in overall survival was not significantly different between groups. The results showed that high PD-L1 expression in bladder cancer was associated with tumor aggressiveness and grade. Despite the inability of the qRT-PCR to show the PD-L1 expression at different locations of tumor tissue, evaluation of PD-L1 mRNA expression by qRT-PCR, which is a highly sensitive and specific assay, appears to be a robust approach. Furthermore, these findings may contribute to a rationale for recommending anti-PD-L1 immunotherapy as an alternative to standard therapy for bladder cancer patients who are most likely to benefit from it.

Prognostic significance of PD-L1 expression as a potential predictor of survival in gastric cancer

Currently, PD-L1 expression in patients with tumors of various localizations is being actively studied. Studies on the expression of PD-L1 detected by clones SP142 and SP263 in gastric cancer (for the drugs atezolizumab and durvalumab, respectively) are rare in the literature. The prognostic role of PD-L1 expression in patients who were not treated with immune checkpoint inhibitors has also not been investigated. To determine the expression level of PD-L1 (clones SP263 and SP142, Roche Ventana) in gastric cancer specimens and evaluate its effect on overall survival in patients who did not receive adjuvant therapy with immune checkpoint inhibitors. The study included 131 patients with a verified diagnosis of gastric cancer. The material obtained from 127 patients was stained with antibodies to PD-L1 SP263, and from 126 patients - with antibodies to PD-L1 SP142. A multivariate Cox regression model with Wald's step-by-step exclusion algorithm was used to evaluate predictors of survival. The total five-year survival rate of patients in the PD-L1-negative tumor group was significantly lower than the total five-year survival rate of patients in the PD-L1-positive tumor group, which was 50.0% and 40.0% also for both clones (p=0.027). An increase in the expression of PD-L1 clone SP263, determined by both the CPS and TPS method, reduces the chances of death by 1.35 times (p=0.02) and 1.61 times (p=0.004), respectively. An increase in the expression of PD-L1 clone SP142, determined by the CPS method, reduces the chances of death by 1.54 times (p=0.005). The survival rate of patients in the group of PD-L1-positive tumors is significantly higher than in patients in the group of PD-L1-negative tumors. Elevated PD-L1 expression, as assessed by the SP263 and SP142 clones, is an important prognostic marker that predicts a higher chance of overall survival for patients, even though these patients are not receiving immune checkpoint inhibitors adjuvant therapy.

Prognostic Significance of PD-L1 Expression in Stage 4 Non-Small-Cell Lung Cancer

Prognostic Significance of PD-L1 Expression in Stage 4 Non-Small-Cell Lung Cancer

Prognostic significance ofPD-L1 expression in pancreatic cancer: evidence from anupdated meta-analysis.

Recent studies revealed that programmed cell death ligand 1 (PD-L1) expression was associated with unfavorable prognosis in various solid tumors, but its clinical relevance for pancreatic cancer has not yet been well established. This meta-analysis summarizes thepotential prognostic value ofPD-L1 in pancreatic cancer. Aquantitative meta-analysis was performed by asystematic search ofdatabases including PubMed, EMBASE, Web ofScience, Cochrane library, Scopus and Ovid for eligible studies on theprognostic significance ofPD-L1 in pancreatic cancer patients. Pooled hazard ratios (HRs) and their 95% confidence intervals (CIs) were calculated to evaluate thestrength ofthelink between PD-L1 expression and clinical prognosis ofpatients. Seventeen eligible studies with 2669 patients were included in our study. Asignificant association was observed between PD-L1 abundance and poor overall survival (OS) ofpatients with pancreatic cancers, with apooled hazard ratio (HR) of1.902, 95% CI: 1.657-2.184. Sensitivity analysis confirmed thereliability ofour results. Subgroup analysis shows that differences in regions and detection methods ofPD-L1 did not change theoverall predictive value ofPD-L1 for poor prognosis in pancreatic cancer patients. This meta-analysis indicated that theexpression ofPD-L1 is associated with aworse OS in pancreatic cancer patients. Additionally, PD-L1 may act as a potential parameter for predicting poor prognosis and thus providing apromising target for anticancer therapy in pancreatic cancer.

Prognostic Significance of PD1, PD-L1 Expression , Pathological Subtypes and Metabolic Activity on 18F-FDG PET/CT in Refractory /Relapsing Pediatric Hodgkin Lymphoma

Background:Hodgkin Lymphoma (HL) is a unique disease entity both in its pathology and the young patient population that it primarily affects. Several meta-analyses have demonstrated that high PD-L1 expression levels are correlated with adverse clinical and pathologic features. Objectives: The aim of this study is to evaluate the correlation between the expression of PD-L1 and clinicopathological features, as well as the prognostic significance of PD-L1 expression with regard to interim PET response in relapsing / refractory pediatric HL. Methods: We measured the expression of PD-1/PD-L1 in the baseline diagnostic samples of children with relapsing/ refractory classical HL. The results were correlated with the pathological subtypes as well as the clinical outcome. Results: Of the 88 included patients, 77% had advanced stage HL. PD-1 expression was detected in 50% of cases, whereas PD-L1 (membranous) was expressed by tumor cells in 60% of the cases, and strongly expressed in 16% of cases. Notably, PD-L1 (cytoplasmic) was detected in 55% of the cases. There was a significant differences in the expression levels of PDL-1 between the different pathological subtypes (p = 0.006). OS of patients with PD-L1expression (Cytoplasmic) was 83% vs 91% in patients with absent expression (P=0.001). There was no prognostic significance of PD-L1 expression with regard to PET response (p=0.31). Conclusion: Although PD-L1 expressions did not show statistically significance with well-established prognostic factors, our preliminary data indicate that pathological subtypes and cytoplasmic expression of PD-L1 may have a prognostic implication on survival in pediatric HL. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Incidence and Prognostic Significance of PD-L1 Expression in High-Grade Salivary Gland Carcinoma.

ObjectivePD-L1 is one of the predictors of immunotherapy efficacy. Our goal was to analyze its expression and prognostic significance in high-grade salivary gland carcinoma (SGC).MethodsPD-L1 expression was evaluated using paraffin-embedded specimens from patients with surgically treated high-grade SGC, and it was scored by the tumor proportion score (TPS), combined positive score (CPS), and immune cell (IC) score. Associations between clinicopathological variables, disease-free survival (DFS), overall survival (OS) and PD-L1 expression were assessed.ResultsTPS≥1% occurred in 47 patients with an incidence of 43.1%, and it was significantly related to an advanced tumor stage. In patients with TPS<1%, TPS ranging from 1% to 20%, and TPS≥20%, the 5-year DFS rates were 36%, 26%, and 13%, respectively, and the difference was significant. In patients with TPS<1%, TPS ranging from 1% to 20%, and TPS≥20%, the 5-year OS rates were 49%, 24%, and 13%, respectively, and the difference was significant. CPS≥1 occurred in 87 patients with an incidence of 79.8%. IC scores of 0, 1, 2, and 3 were noted in 24 (22.0%), 37 (33.9%), 31 (28.4%), and 17 (15.6%) patients, respectively. Both CPS and IC scores had no impact on DFS or OS.ConclusionsThe expression of PD-L1 in tumor cells of high-grade SGCs was not uncommon, and it was significantly associated with tumor stage. PD-L1 expression in tumor cells rather than in immune cells indicated a poor prognosis.

Prognostic value of programmed death-ligand 1 status in Japanese patients with renal cell carcinoma

BackgroundProgrammed death-ligand 1 (PD-L1) positivity is associated with poor prognosis in renal cell carcinoma (RCC). Because the prognostic impact and effect of confounding factors are less known, we investigated the prognostic significance of PD-L1 expression in Japanese patients with recurrent/metastatic RCC who started systemic therapy in 2010–2015.MethodsThis multicenter, retrospective study recruited patients from 29 Japanese study sites who had prior systemic therapy for RCC (November 2018 to April 2019) and stored formalin-fixed paraffin-embedded primary lesion samples. The primary outcome was overall survival (OS) by PD-L1 expression. Secondary outcomes included OS in subgroups and duration of first- and second-line therapies by PD-L1 expression. OS distributions were estimated using Kaplan–Meier methodology.ResultsPD-L1 expression (on immune cells [IC] ≥ 1%) was observed in 315/770 (40.9%) patients. PD-L1 positivity was more prevalent in patients with poor risk per both Memorial Sloan Kettering Cancer Center [MSKCC] and International Metastatic RCC Database Consortium, and high-risk pathological features (higher clinical stage, nuclear grade and sarcomatoid features). Median OS for PD-L1–positive patients was 30.9 months (95% CI 25.5–35.7) versus 37.5 months (95% CI 34.0–42.6) for PD-L1–negative patients (HR 1.04 [90% CI 0.89–1.22, p = 0.65]; stratified by MSKCC risk and liver metastases). Propensity score weight (PSW)-adjusted OS was similar between PD-L1–positive and –negative patients (median 34.4 versus 31.5 months; estimated PSW-adjusted HR 0.986).ConclusionsThis study suggests PD-L1 status was not an independent prognostic factor in recurrent/metastatic RCC during the study period because PD-L1 positivity was associated with poor prognostic factors, especially MSKCC risk status.

Abstract 3192: PD-L1 is an independent prognostic marker in Middle Eastern PTC and its expression is upregulated by BRAFV600E mutation

Abstract Background: PD-L1 inhibition is a promising therapeutic target whose efficacy has been demonstrated in several cancers. This study was conducted to evaluate the prognostic significance of PD-L1 expression in a large cohort of Middle Eastern PTC patients and to explore correlation of PD-L1 and BRAFV600E mutations in PTC tumors and cell lines. Methods: Immunohistochemistry was performed to assess PD-L1 protein expression in PTC. We further conducted in vitro analysis to investigate the role of PD-L1 in regulating BRAFV600E in PTC cell lines. Results: PD-L1 over-expression was noted in 32.4% (473/1458) of cases and significantly associated with adverse clinico-pathological parameters such as tall cell variant, extra-thyroidal extension and lymph node metastasis. Importantly, PD-L1 was found to be an independent poorer prognostic marker. We also found PD-L1 to be significantly associated with BRAF mutation and patients with co-existing PD-L1 over-expression and BRAF mutation had a poor disease-free survival compared to patients with BRAF mutation alone. In vitro analysis showed high expression of PD-L1 in BRAF mutated PTC cell lines compared to BRAF wild-type cell line. Inhibition of BRAF using vemurafenib induced PD-L1 expression in BRAF mutated cell lines without affecting cell growth. Knockdown of PD-L1 in BRAF mutated cell lines significantly decreased the cell growth and induced apoptosis. Conclusion: Our data suggests that PD-L1 might represent a useful prognostic marker in Middle Eastern PTC and PD-L1 inhibition could be a potential therapeutic option for aggressive PTC cancers, such as tall cell variant, BRAF mutation positive patients that are unresponsive to standard treatment. Citation Format: Tariq Masoodi, Abdul K. Siraj, Sandeep Kumar Parvathareddy, Poyil Pratheeshkumar, Sasidharan Padmaja Divya, Rafia Begum, Roxanne Diaz, Thangavel Saravanan, Khadija Al-Obaisi, Sarah Siraj, Saud Azam, Zeeshan Qadri, Khawla S. Al-Kuraya. PD-L1 is an independent prognostic marker in Middle Eastern PTC and its expression is upregulated by BRAFV600E mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3192.

Clinical Significance of PD-1 and PD-L1 Expression and Ongoing Interaction in the Tumor Microenvironment in Diffuse Large B Cell Lymphoma (DLBCL) Treated with R-CHOP

Background: PD-1 blockade has demonstrated antitumor activity in diffuse large B-cell lymphoma (DLBCL). In order to select patients who are more likely to respond to PD-1 blockade, predictive biomarkers are being intensively pursued. PD-1 and PD-L1 expression in DLBCL treated with R-CHOP as standard-of-care has been examined in several studies. However, only overall PD-1+ cells but not T-cell specific PD-1 expression have been quantitated, and results of the prognostic significance of PD-L1 expression have been inconsistent in DLBCL patients. Whether ongoing PD-1/PD-L1 interaction in tumors contributes to the adverse prognostic effect of PD-1 and PD-L1 expression is unknown.Patients and Methods: Tissue microarray (TMA) sections ofdiagnostic samples from 414 patients with de novo DLBCL treated with R-CHOP were fluorescently stained with CD3 (T cell marker), PD-1, and PD-L1. Positive cells and PD-1/PD-L1 interaction were quantitatively assessed by the Automated Quantitative Analysis (AQUA) algorithms. To characterize PD-1/PD-L1 expression in each sample, CD3+, PD-1+, PD-L1+, and PD-1+CD3+ (double positive, i.e., PD-1+ T) cell numbers were divided by total nucleated cells (DAPI+) in the representative tumor areas. Ongoing PD-1/PD-L1 interactions were evaluated by the proximity of PD-1+ T cells to the PD-L1+ compartments and proportion of PD-1+ T cells co-localized with PD-L1, generating an interaction score for each sample. Biomarker expression and interaction scores were correlated with patient survival.Results: CD3+, PD-1+, PD-L1+, and PD-1+CD3+ cells were identified in 90%, 30%, 53%, and 18% of the cohort, respectively. The mean percentages of CD3+, PD-1+, PD-L1+, and PD-1+CD3+ cells in DLBCL tissues were 12.1%, 0.44%, 3.6%, and 0.19%, respectively. Activated B-cell-like DLBCL had a significantly higher mean percentage of PD-L1+ cells, but not PD-1+CD3+ cells, compared to germinal center B-cell-like DLBCL (p=0.0012). Three prognostic tiers were identified. Firstly, absence to very low percentage (0-3.5%) of tumor-infiltrating CD3+ T cells in the tissues was associated with poorer overall survival (OS) of DLBCL patients (p=0.028). CD3high DLBCL (>3.5% of all cells were CD3+) was associated with significantly higher percentages of PD-L1+ and PD-1+ cells (p<0.0001 and p=0.005, respectively). Secondly, in CD3high DLBCL, presence of PD-1+ T cells correlated with significantly poorer OS and progression-free survival (PFS) of patients (p=0.028 and p=0.0099, respectively). In contrast, presence/absence of PD-1+ non-T cells was not prognostic. Presence of PD-1+ T cells in CD3high DLBCL was associated with a higher mean percentage of PD-L1+ cells (p=0.019). However, PD-1/PD-L1 interaction scores did not add to the prognostic effect. This may suggest that phenotype of PD-1/PD-L1 interaction is not a biomarker to specify the immunosuppressive role of the PD-1/PD-L1 axis. Lastly, in CD3high DLBCL cases with PD-1−negative T cells, PD-L1 positivity correlated with significantly poorer OS and PFS of patients (p=0.0034 and p=0.0059, respectively), although PD-L1+ was not associated with non-T PD-1 expression either, suggesting PD-1−independent function of PD-L1. In the overall cohort, presence of PD-1+ T cells was associated with a trend of poorer PFS (p=0.079), whereas PD-L1 expression was not prognostic.Conclusions: PD-1 expression in T cells and lack of tumor-infiltrating CD3+ T cells are associated with significantly poorer survival of DLBCL patients. In addition, our data suggest that PD-1 can be a prognostic marker independent of PD-1/PD-L1 co-localization, and that PD-L1 has other PD-1-independent inhibitory functions. These results demonstrate the importance of both T-cell influx and antitumor function in prolonging the survival of DLBCL patients, and provide rationales for PD-1 blockade and immunotherapies activating T cell-mediated immune responses in DLBCL. DisclosuresTran:Genoptix, Inc: Employment. Adams:Navigate BioPhama Services, Inc: Employment. Roscoe:Navigate BioPhama Services, Inc: Employment. Hsi:Seattle Genetics: Consultancy, Honoraria, Speakers Bureau; Abbvie: Research Funding; Eli Lilly and Co.: Research Funding; Cellerant Therapeutics: Research Funding. Piris:Kura Oncology: Research Funding. Winter:Glaxo-Smith-Kline: Research Funding; Merck: Research Funding. Vaupel:Genoptix Laboratory: Employment. Dakappagari:Genoptix, Inc: Employment.

The prognostic significance of PD-L1 expression on tumor and immune cells in Merkel cell carcinoma.

The aim of this study was to evaluate prognostic factors in patients with non-metastatic Merkel cell carcinoma (MCC), with a particular focus on immunological markers such as TILs subtyping (CD3, CD8, CD68, FoxP3, PD-L1 and PD-1) and MCPyV. Patients treated for a non-metastatic MCC with oncologic surgical resection followed or not by adjuvant radiotherapy between 01/2007 and 12/2018 were analyzed. Local and regional control (LC, RC), distant metastasis-free survival (DMFS) and overall survival (OS) were evaluated. Clinical variables analyzed included age, gender, performance status, comorbidity, tumor size, location and presentation type, extension, oncologic resection and adjuvant radiotherapy. Pathological variables analyzed included type of tumor-infiltrating lymphocytes, CD3, CD8, CD68, PD-L1 expression on immune cells and tumors cells, PD-1, FoxP3 and MCPyV, assessed with immunohistochemistry (IHC). 77 patients were included. After a median follow-up of 18months (range 0.2-144), the 1-year LC, RC, DMFS and OS were 83%, 60%, 82% and 75%, respectively. In multivariate analysis, a percentage of PD-L1 expression by immune cells ≥ 1% was significantly correlated with improvement of RC (p = 0.012), DMFS (p = 0.003) and OS (p = 0.006). Adjuvant radiotherapy significantly improved DMFS (p = 0.021) and OS (0.041) rates. There was a correlation between the presence of MCPyV + and the expression of PD-L1 on IC (p = 0.05) and TC (p = 0.03). PD-L1 expression by immune and tumor cells in non-metastatic MCC seems to significantly improve outcome in patients who did not received PD-1/PD-L1 inhibitors. Prospective studies are needed to confirm our hypothesis.

83P Evaluation of the prognostic significance of PD-L1 expression after combined radiochemotherapy in patients with stage III NSCLC

83P Evaluation of the prognostic significance of PD-L1 expression after combined radiochemotherapy in patients with stage III NSCLC

PD-L1 in Breast Cancers and its Prognostic Significance

Breast cancer is the most common malignancy in females globally. Various factors are responsible for its developmentwhich include both genetic and hormonal causes. An important discovery is the role of the PD-1/PD-L1 axis in thedevelopment of cancers. The PD-1-/PD-L1 pathway plays a part in allowing tumour cells escape from the host’s immuneresponse and hence permits the proliferation of tumour cells. PD-L1 expression has been observed in various breast cancersat distinct levels such as in tissues and in blood. Different methods have been utilized for its detection includingimmunohistochemistry, RNA sequencing and ELISA, amongst others. The results have been conflicting regarding theexpression of PD-L1 and the prognosis of breast cancer based on parameters such as overall survival and disease freesurvival. Different immunotherapies have also emerged as a new modality to treat breast cancer. This review intends toexplore the prognostic significance of PD-L1 expression in breast cancers.

Clinicopathological and prognostic significance of PD-L1 expression in colorectal cancer: a meta-analysis

PurposeTo systematically evaluate the correlation between PD-L1 expression and clinicopathological features and prognosis of colorectal cancer (CRC).MethodsSeven databases (PubMed, Cochrane Library, EMBASE, Web of Science, CBM, Wanfang, and CNKI) were searched through May 2020. Risk of bias and quality of evidence were assessed by using the Newcastle–Ottawa scale (NOS), and meta-analysis was carried out by using the Review Manager 5.3 software on the studies with the quality evaluation scores ≥ 6. Meta-regression analysis was used to determine the independent role of PD-L1 expression on CRC prognosis after adjusting clinicopathological features and treatment methods.ResultsA total of 8823 CRC patients in 32 eligible studies. PD-L1 expression was correlated with lymphatic metastasis (yes/no; OR = 1.24, 95% CI (1.11, 1.38)), diameter of tumor (≥ 5 cm/< 5 cm; OR = 1.34, 95% CI (1.06, 1.70)), differentiation (high–middle/low; OR = 0.68, 95% CI (0.53, 0.87)), and vascular invasion (yes/no; OR = 0.80, 95% CI (0.69, 0.92)). PD-L1 expression shortened the overall survival (hazard ratio (HR) = 1.93, 95% CI (1.66, 2.25)), disease-free survival (HR = 1.76, 95% CI (1.50, 2.07)), and progression-free survival (HR = 1.93, 95% CI (1.55, 2.41)). Meta-regression showed that PD-L1 expression played a significant role on poor CRC OS (HR = 1.95, 95% CI (1.92, 3.98)) and disease-free survival (HR = 2.14, 95% CI (0.73, 4.52)).ConclusionPD-L1 expression independently predicted a poor prognosis of CRC.

Histopathologic PD-L1 Tumor Expression and Prognostic Significance in Nonmelanoma Skin Cancers: A Systematic Review.

PD-L1 and PD-1 inhibitors are being increasingly used to treat a variety of nonmelanoma skin cancers (NMSCs). This systematic review summarizes PD-L1 expression in NMSCs and determines its use for prognosis using targeted immunotherapy. A primary search of peer-reviewed English-language medical literature was conducted for studies on PD-L1 tumor expression in biopsied or excised NMSCs. Fifty-nine articles met criteria for inclusion. PD-L1 expression in advanced NMSCs ranged from 22%-89% for basal cell carcinomas, 42%-50% for Merkel cell carcinomas, and 26%-100% for squamous cell carcinomas. Study limitations included clone heterogeneity across studies, complicating comparison of PD-L1 expression. Differences were also noted in the selection of tumor reactivity threshold. We conclude that there is insufficient evidence to determine the prognostic significance of PD-L1 expression in NMSCs as a whole, but this remains a promising area. More investigation into the role of tumor PD-L1 as a biomarker for predicting clinical response to PD-L1 and PD-1 inhibitors in NMSCs is needed.

Significance of Programmed Death Receptor Ligand One Expression in Brain Metastases of Non-Small Cell Lung Carcinoma

Survival in patients with metastatic non-small cell lung carcinoma (NSCLC) has considerably increased in recent years, in part due to the advent of programmed death/programmed death ligand one (PD-1/PD-L1) inhibitors. There is increasing evidence that patients with NSCLC brain metastases (BMs) also benefit from these novel therapies. PD-L1 expression as assessed by immunohistochemistry is known to predict response to PD-L1/PD-1 checkpoint inhibitors. However, it is not known whether this biomarker has prognostic significance in patients with BMs. Therefore, the aim of this study was to assess whether PD-L1 expression predicts survival in patients with NSCLC BMs treated with radiotherapy or neurosurgery as well as PD-1/PD-L1 inhibitors, after adjusting for the lung-Graded Prognostic Assessment (lung-GPA). This was a multi-institutional retrospective study. Patient records from three hospitals were reviewed to identify NSCLC BM patients who were treated with PD-1/PD-L1 inhibitors after intracranial treatment (resection, SRS (stereotactic radiosurgery/radiotherapy (SRS/SRT)), or whole-brain radiotherapy) but before intracranial progression. PD-L1 expression was considered positive in case of >1% histopathological staining. Cox proportional hazards model was used to assess prognostic significance of PD-L1 expression. Forty-eight patients with available PD-L1 expression were identified; median follow-up in this cohort was 24.7 months. Intracranial treatment consisted of SRS (n = 37), SRT (n = 3), resection (n = 7), or WBRT (n = 1). Intracranial treatment for newly diagnosed BMs was given to 30 patients; while 18 were treated for a recurrent BM. PD-L1 expression was positive in 33 patients (69%). In this cohort, median survival was 21.7 months. When split by lung-GPA, median survival in months was as follows: GPA 0-1: 11.4 (n = 6), GPA 1.5 – 2: 16.3 (n = 22), GPA 2.5 – 3: median not reached (n = 17); GPA 3.5 – 4: 14.6 (n = 3). In univariate analysis, PD-L1 expression was a borderline significant predictor for overall survival (HR = 0.44; 95% CI 0.19 – 1.00; p = 0.05). In multivariate analysis, PD-L1 was prognostic for overall survival (HR = 0.36, 95% CI = 0.14 – 0.90; p = 0.03) after correcting for lung-GPA, type of intracranial treatment, and newly diagnosed vs recurrent BMs. PD-L1 expression may be a prognostic factor independent of lung-GPA in patients with NSCLC BMs who underwent treatment with PD-1/PD-L1 checkpoint inhibitors. Larger studies are required to validate this finding.

Abstract 4038: In-depth PD-L1 scoring reveals potential correlations between tumor-intrinsic PD-L1 and myeloid-inflamed profiles in head and neck cancer

Abstract Programmed cell death protein-1 (PD-1) inhibition has been showing encouraging results for recurrent/metastatic head and neck squamous cell carcinoma (HNSCC), which simultaneously requires the development of predictive biomarkers to guide selection of conventional and immune checkpoint therapies. Most recently, PD-L1 IHC scoring of tumor and inflammatory cells, but not of tumor cells alone, has been reported as effective metrics for selection between PD-1 inhibition and standard combination therapy of platinum/5-FU/cetuximab for HNSCC. Toward establishment of PD-L1 score-based biomarkers, the present study is aimed to evaluate in-depth PD-L1 profiles of tumor and immune cells in association with immune complexity profiles of HPV-positive and negative HNSCC via 12-marker multiplex immunohistochemistry (IHC) and image cytometry. As previously reported (Tsujikawa et al. Cell Reports. 2017), oropharyngeal HNSCC cases were divided into three clusters of lymphoid-, hypo-, and myeloid-inflamed profiles based on cell densities of immune cell lineages. Averages of PD-L1+ percentages in immune cells were 5.3, 7.1, and 12.8 in lymphoid-, hypo-, myeloid-inflamed groups, respectively. High PD-L1 expression on immune cells was observed in CD163+CSF1R+ tumor-associated macrophages and mature dendritic cell populations particularly in intra-tumor regions. Interestingly, averages of PD-L1+ percentages in tumor cells were 0.17, 0.64, and 5.3 in lymphoid-, hypo-, myeloid-inflamed groups, respectively, suggesting that tumor-intrinsic PD-L1 expression without lymphoid-inflamed profiles was potentially associated with myeloid-inflamed profiles. To further evaluate the prognostic significance of PD-L1 expression with low lymphoid-inflamed profiles, we evaluated the the Cancer Genome Atlas (TCGA) HNSCC cohort (N = 528), and observed that high PD-L1 expression with low CD8+ T cell cytolytic activity was associated with short overall survival. Immune complexity analysis for longitudinal specimens from a nivolumab-resistant case with PD-L1 expression on tumor cells revealed the potential involvement of myeloid-inflamed status, suggesting the presence of differential PD-L1 profiles between tumor and immune cells in the context of lymphoid/myeloid-inflamed status. Those findings together indicate that combination of in-depth PD-L1 scoring and immune complexity profiling may contribute to biomarker development toward optimized management for HNSCC.Acknowledgement: This project was supported by the Japan Society for the Promotion of Science Grant-in-Aid (17H07016). Citation Format: Takahiro Tsujikawa, Tsutomu Kawaguchi, Kanako Yoshimura, Junichi Mitsuda, Akihito Aarai, Shigeru Hirano. In-depth PD-L1 scoring reveals potential correlations between tumor-intrinsic PD-L1 and myeloid-inflamed profiles in head and neck cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4038.

PD-L1 expression by immunohistochemistry in salivary duct carcinoma

BackgroundImmune checkpoint inhibitors play an increasing role in oncologic care. PD-L1 expression is associated with survival and predicts response to PD-1 or PD-L1 inhibitors in a variety of tumors. Our aim is to evaluate the frequency and prognostic significance of PD-L1 expression in salivary duct carcinoma. DesignWe retrospectively evaluated the expression of PD-L1 by two different antibodies (PD-L1 28–8 and PD-L1 22C3) in salivary duct carcinomas. PD-L1 expression in at least 1% of tumor cells was considered immunoreactive. Kaplan-Meier analysis was performed to determine the impact of PD-L1 expression on survival; differences between survival curves were assessed by the chi-square test, and pairwise comparisons of factors were assessed with the log-rank test. ResultsA total of 113 patients' specimens were evaluated. Seventy-six (76%) of the patients were male. Mean age at time of presentation was 61.2 (SD = 12.4) years. PD-L1 expression was found in 26% of the samples. Median follow-up time was 36.6 months (range = 1.4–249 months). Overall survival at 3, 5 and 10 years were 52.6%, 37.9% and 25.6%, respectively. There was no statistical difference in survival between patients with PD-L1-immunoreactive tumors and those without, regardless of which antibody was used (chi2 result for all plots: p = 0.53; log rank test for pairwise comparison: p > 0.256). ConclusionIn our analysis, PD-L1 expression occurred in a small proportion of salivary duct carcinomas, usually at low levels, and did not correlate with survival. Its predictive value and utility in selecting patients with salivary duct carcinoma who might benefit from PD-1/PD-L1 inhibitors warrants further investigation.

P3.13-28 Heterogeneity, Prevalence and Prognostic Significance of PDL1 Expression in Early Resected NSCLC

P3.13-28 Heterogeneity, Prevalence and Prognostic Significance of PDL1 Expression in Early Resected NSCLC

Clinicopathological and prognostic significance of PD-L1 expression in sarcoma

Programmed cell death-ligands 1 (PD-L1) is a key immune checkpoint protein and a promising therapeutic target for malignancy tumor immunotherapy. The prognostic value of PD-L1 in patients with bone and soft tissue sarcoma remains controversial. Therefore, this meta-analysis is conducted to evaluate the associations of PD-L1 expression with overall survival (OS), progression-free survival (PFS), and clinicopathological characteristics of sarcomaA comprehensive literature search of PubMed, Web of Science, Embase, and Cochrane Library was conducted for relevant studies. A total of 14 studies published from 2013 to 2017 were included. The pooled hazard ratios (HRs) with 95% confidence intervals (CIs) were extracted from included studies to assess the association between PD-L1 expression and OS, PFS of patients with sarcoma. Other relevant data were extracted to evaluate the correlations of PD-L1 expression with risk and clinicopathological characteristics of sarcoma. Stata 12.0 software was applied to calculate the strength of association between PD-L1 expression and sarcoma.In total, 14 articles containing 15 independent studies and 1,451 patients were included in this meta-analysis. We found that the high PD-L1 expression was associated with poorer overall survival (HR 1.27, 95% CI: 0.70–1.84 P = .000) and poorer events-free survival (HR 2.05, 95% CI: 1.55–2.70, P = .000) in bone and soft-tissue sarcoma patients. Additionally, we conducted subgroup analysis according to histology type, ethnicity, target of PD-L1 assessment, cutoff, the significant correlations with poor overall survival and events-free survival were also observed. In contrast none of the clinicopathological characteristics (gender, age, tumor site, tumor grade, tumor depth, tumor necrosis rate, metastasis, recurrence, chemotherapy, radiotherapy) was found to be associated with PD-L1 expression in our analysis.The findings from this meta-analysis indicate that PD-L1 expression might be a useful predicative factor of poor prognosis for patients with bone and soft tissue sarcoma.

40 Prognostic significance of PD-L1 expression in meningioma for tumor recurrence; associated with hypoxia and NFKB2 activation

Estimation of tumor recurrence in meningioma patients is one of the important clinical challenges. The prognostic impact of immune modulatorymolecule PD-L1 in several malignancies has been demonstrated. We studied the association of PD-L1 expression in meningioma with tumor recurrence and the underlying mechanism of its activation. Immunohistochemical staining(IHC) was performed for detection of PD-L1and NFKB2 on whole sections of meningiomas diagnosed between1998-2016 at TorontoWesternHospital. The biologic role of hypoxia in activation of PD-L1 in meningioma was investigated using gene set enrichment analysis(GSEA)-based on RNAseq data in validation cohorts. We analyzed a total of 93 meningioma cases: F/M ratio58/35;WHOgrade I(41),II(43),III(9),42(47%)cases with tumor recurrence and median follow up was 6.97yrs. PD-L1 expression on tumor cells(PD-L1TC) in 33(35%) cases was identified with distinctive patchy distribution. Univariate analysis indicated expression of PD-L1TC as a prognostic factor for tumor recurrence(p&lt;0.0001). Multivariate analysis showed that PD-L1TC expression is an independent prognostic factor for tumor recurrence after adjusting for extent of resection(EOR),WHO grade and maximum tumor diameter(p&lt;0.0001). Analysis of RNAseq data of two GEOmeningioma studies demonstrated prominent expression of NFKB activation associated with PD-L1expression. IHC analysis confirmed increased expression of NFKB2 protein in 26(30%)cases,which correlated with PD-L1TC expression(p=0.02). Furthermore,GSEAon a RNAseq data of 88 sporadic meningiomas using Hypoxia gene signature of HUVEC cells we found that the hypoxic sporadic meningiomas have significantly elevated PD-L1 expression(p&lt;0.001). Our data strongly suggest that PD-L1TCexpression serves as a significant prognostic marker for tumor recurrence and. We found that hypoxia andNFKB2 activation are potential underlying mechanisms. These results also provide a rationale for potential adjuvant therapeutic role for PD-L1 inhibitors in meningioma.