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Although there are immune checkpoint inhibitors (ICIs) available for the treatment of renal cell carcinoma (RCC), the utility of PD-L1 detection by immunohistochemistry (IHC) as a predictive biomarker in clear cell RCC (ccRCC) remains controversial. Nevertheless, alternative methods for PD-L1 detection, such as RNA sequencing (RNA-Seq), may be clinically useful in ccRCC; therefore, we sought to determine the ability of RNA-Seq to accurately and sensitively detect PD-L1 expression across different ccRCC clinical samples in comparison with IHC.Patients with ccRCC (n=127) who received treatment from Washington University in St. Louis between 2018 and 2020 were identified. Tumors from these patients were analyzed using RNA-Seq and IHC.PD-L1 detection by RNA-Seq strongly correlated with IHC (P.001), which was further validated using two independent datasets. Furthermore, RNA-Seq analysis identified an immune-enriched (higher PD-L1 positivity) and an immune-desert (lower PD-L1 positivity) microenvironment of ccRCC, which also correlated with IHC (P.00001).The results demonstrate the ability of RNA-Seq to detect PD-L1 in various ccRCC clinical samples compared to IHC. Ultimately, these findings suggest that PD-L1 detection by RNA-Seq can be further developed to determine the clinical utility of this methodology in ccRCC.

The action of checkpoint inhibitors is based on activation of T cell antitumor immunity, and, therefore, the search for markers of lymphocyte functional activity before starting the therapy is highly relevant. Determination of the PD-L1 expression in tumor tissues reflects immunosuppressive activity of malignant cells, and it is used as a predictive marker in clinical practice. The ratio of neutrophils to lymphocytes in tumor tissue and in peripheral blood can also indicate the activity of adaptive immunity and correlates with the efficacy of therapy. It has been shown that a high level of interleukin 1 beta in the tumor microenvironment is associated with immunosuppression of lymphocytes and, possibly, reflects the activity of the tumor microenvironment. The aim of this work is to study the relationship between tumor expression of PD-L1, the concentration of serum interleukin-1 beta and the ratio of neutrophils and lymphocytes in peripheral blood.Before starting therapy with checkpoint inhibitors in patients with various solid tumors (n = 50), the serum level of interleukin-1 beta was determined by ELISA (ELISA-Best, Novosibirsk, Russia), expression of PD-L1 in the tumor by immunohistochemical method, complete blood count was performed using cytometry. Statistical analysis was performed in GraphPad Prism 6 (Graph Pad Software, USA) using the statistical methods of Fisher, Mann-Whitney, and Spearman.The average value of the index of the ratio of neutrophils and lymphocytes (NLR) in peripheral blood was 2.65± 0.21 (95% CI 2.22-3.07). The index value of more than 3.5 was found in 18% (9/50) of patients. The mean value of the PD-L1 expression level was 23.02±4.52% (95% CI 13.86-32.18). Expression of PD-L1 in tumor tissue was detected in 60.1% (25/40) of patients, among whom an increased expression of more than 50% was detected in 20.0% (5/25) of cases. A positive weak correlation was found between the concentration of interleukin 1 beta and the number of leukocytes (r = 0.34; p = 0.019) and index (r = 0.32; p = 0.029). The level of PD-L1 expression in tumor tissue also had a weak positive correlation with the serum interleukin 1 beta concentration (r = 0.33; p = 0.037) and the neutrophil-lymphocyte ratio (r = 0.33; p = 0.034). In the group of patients with PD-L1 expression > 5%, the mean value of the concentration of interleukin 1 beta was 1.65±0.62 pg/ml, and the mean value of the index was 4.26±0.94 х 10 9/l, which exceeds the values groups with undetectable PD-L1, but the differences were not statistically significant.The obtained result may indicate the influence of the immunosuppressive properties of the tumor on the state of the patient's immunity. Comprehensive determination of tumor PD-L1 expression, serum interleukin 1 beta concentration and the ratio of neutrophils and lymphocytes in peripheral blood can be used as an assessment of the patient's immune status before starting treatment with checkpoint inhibitors.

Immune checkpoint inhibitors (ICI) have demonstrated efficacy in the treatment of solid cancers. However, there is no unified predictive biomarker available for ICIs. We aimed to compare the prognostic impact of using three PD-L1 antibodies (SP142, SP263, and 22C3) for immunohistochemical (IHC) analysis. We retrospectively investigated tumor tissues derived from 316 breast cancer cases, by constructing tissue microarrays and by performing IHC staining. The immune-cell expression rate (for SP142 and SP263) and combined proportional score (for 22C3) were evaluated, and survival outcomes were analyzed. Prediction models were developed, and values of Harrel’s c-index and areas under curves were calculated to compare the discriminatory power. Negative PD-L1 expression based on the 22C3-IHC assay was determined to be an independent prognostic marker for recurrence-free survival (RFS, P = 0.0337) and distant metastasis-free survival (DMFS, P = 0.0131). However, PD-L1 expression based on SP142- and SP263-IHC assays did not reveal a prognostic impact. Among the three antibodies, adding PD-L1 expression data obtained via 22C3-IHC assay to the null model led to a significant improvement in the discriminatory power of RFS and DMFS. We suggest that PD-L1 expression based on the 22C3-IHC assay is a superior prognostic marker than that based on SP142- and SP263-IHC assays.

Primary adrenal diffuse large B-cell lymphoma (PA-DLBCL) is rare. We investigate 23 Japanese patients with PA-DLBCL to understand the clinicopathologic features and biological behavior of this disease. The 17 males and 6 females had a median age of 74 years (range: 40 to 86 y). Tumor cells harbored Epstein-Barr virus-encoded small RNA (EBER) in 9 (39%) samples, including samples from the 2 patients with methotrexate-associated B-cell lymphoproliferative disorder. Programmed cell death ligand 1 (PD-L1) expression was detected in tumor cells of 6 (26%) samples, including 1 EBER+ and 5 EBER- samples. Four (17%) patients exhibited an intravascular proliferating pattern, and all 4 patient samples showed positive staining for PD-L1 in tumor cells. Among those patients, 3 showed intravascular proliferating pattern accompanied by a diffuse extravascular proliferation of tumor cells, and 1 patient was diagnosed with intravascular large B-cell lymphoma. We divided the 23 patients into 3 groups: EBER+ (n=9, 39%), EBER-PD-L1+ (n=5, 22%), and EBER-PD-L1- (n=9, 39%). A comparison of the outcomes among the 3 groups showed significant differences in overall survival (P=0.034). The EBER+ group had the worst prognosis, and the EBER-PD-L1- group had the best prognosis. We also compared the outcomes among the 3 groups that received rituximab-containing chemotherapies. Both the overall survival and progression-free survival were significantly different among these groups (P

Here, we used pre-treatment CT images to develop and evaluate a radiomic signature that can predict the expression of programmed death ligand 1 (PD-L1) in non-small cell lung cancer (NSCLC). We then verified its predictive performance by cross-referencing its results with clinical characteristics. This two-center retrospective analysis included 125 patients with histologically confirmed NSCLC. A total of 1287 hand-crafted radiomic features were observed from manually determined tumor regions. Valuable features were then selected with a ridge regression-based recursive feature elimination approach. Machine learning–based prediction models were then built from this and compared each other. The final radiomic signature was built using logistic regression in the primary cohort, and then tested in a validation cohort. Finally, we compared the efficacy of the radiomic signature to the clinical model and the radiomic-clinical nomogram. Among the 125 patients, 89 were classified as having PD-L1 positive expression. However, there was no significant difference in PD-L1 expression levels determined by clinical characteristics (P = 0.109–0.955). Upon selecting 9 radiomic features, we found that the logistic regression-based prediction model performed the best (AUC = 0.96, P

Background Programmed cell death ligand‐1 (PD‐L1) is a useful biomarker in non‐small cell lung cancer (NSCLC) patients who would probably benefit from immunotherapy. In most patients with advanced stage NSCLC, only small biopsy specimens were available for the evaluation of PD‐L1 expression. In this study, we evaluated the feasibility and reliability of PD‐L1 testing on small biopsy samples. Methods Small specimens of advanced NSCLC patients obtained via endobronchial ultrasound‐guided transbronchial needle aspiration (EBUS‐TBNA), endobronchial biopsy (EBB), or computed tomography (CT)‐guided core‐needle biopsy were collected. Tumor cell count and tissue sufficiency for PD‐L1 immunohistochemistry (IHC) were evaluated and compared. The clinical course of patients who received immunotherapy in the study population was also examined. Results Tissue acquisitions for PD‐L1 testing in three groups were all above 90%, with no statistically significant differences. The PD‐L1 expressions levels were concordant in most patients with more than one sample (8/11). In the EBB group, PD‐L1‐positive patients had higher objective response rate (ORR) (53.2% vs. 26.9%, p = 0.048) and longer progression‐free survival (PFS) (312 vs. 179 days, p = 0.035) than PD‐L1 negative patients. In the core needle biopsy group, patients with positive PD‐L1 expression also trended to have higher ORR and longer PFS. However, in the EBUS‐TBNA group, both ORR and PFS were similar between patients with positive or negative PD‐L1 expression. Conclusions This study showed that EBUS‐TBNA, EBB, and core needle biopsy provides adequate samples for PD‐L1 testing. The predictive value of PD‐L1 expression on different small samples still warrants further studies., The predictive value of PD‐L1 expression tested on different specimens were compared. The PFS in positive and negative PD‐L1 expression patients in computed tomography (CT) guided core‐needle biopsy, transbronchial biopsy (EBB), and endobronchial ultrasound‐guided transbronchial needle aspiration (EBUS‐TBNA) group were 354 vs 195 days (p = 0.410), 312 vs. 179 days (p = 0.035), 213 vs. 192 days (p = 0.594) separately.

Several immune checkpoint inhibitors targeting programmed death ligand 1 (PD-L1)/programmed death 1 have successfully improved the prognosis of oesophageal squamous cell carcinoma (ESCC) with approval in certain countries. However, whether the expression of PD-L1 is associated with the degree of benefit is unclear yet and a unified standard of antibody and cut-off value of PD-L1 detection is also lacking. The current meta-analysis then aimed to explore the association between PD-L1 expression and clinicopathological features as well as prognosis in ESCC. A systematic search on PubMed, Embase, Cochrane Library and Web of Science databases was performed up to 30 March 2021. The correlation between PD-L1 expression and clinicopathological features, as well as prognosis in ESCC, was estimated with the random-effects model. A total of 5368 patients from 31 retrospective studies were enrolled. The overexpression of PD-L1 was significantly associated with lymph node metastasis (OR 1.342, 95% CI 0.995 to 1.809, p=0.050) and distant metastasis (OR 1.516, 95% CI 1.001 to 2.294, p=0.050). The pooled HR showed that PD-L1 overexpression was significantly correlated with poor overall survival (OS) of patients with ESCC (HR 1.306, 95% CI 1.108 to 1.539, p The overexpression of PD-L1 was correlated with lymph node and distant metastasis as well as poor survival of ESCC.

Cemiplimab may significantly increase overall survival in the first-line treatment of advanced non-small cell lung cancer (NSCLC) with a PD-L1 level of at least 50%. Therefore, there is a need to consider the cost-effectiveness of using this therapy for this indication. This Markov model was built to estimate the cost and effectiveness of cemiplimab vs. chemotherapy in the first-line treatment of advanced NSCLC based on the data from the EMPOWER-Lung 1 trial. Life-years (LYs), quality-adjusted LYs (QALYs) and lifetime costs were estimated. One-way and probabilistic sensitivity analyses were performed to evaluate the model uncertainty. Additional subgroup analyses were performed. Treatment of advanced NSCLC with cemiplimab added 0.546 QALYs (1.492 LYs) and resulted in an incremental cost of $22,069.804 compared with chemotherapy, which was associated with an incremental cost-effectiveness ratio of $40,390.412 per QALY gained. The results of one-way sensitivity analysis found that the cost of cemiplimab was the most sensitive factor in our study. The probabilistic sensitivity analysis showed that the probability of cemiplimab being cost-effective was 100%. The subgroup analysis demonstrated that high PD-L1 expression (≥ 90%, > 60 to

BACKGROUND: Durvalumab is an anti-PD-L1 immune checkpoint inhibitor approved for consolidation therapy for patients with stage III non-small cell lung cancer (NSCLC) after chemoradiation. The purpose of our study was to evaluate the association between the degree of tumor PD-L1 expression and outcomes of stage III NSCLC patients treated with durvalumab. METHODS: We conducted a retrospective analysis of all the patients who received durvalumab between July 2017 and July 2019 at our facilities and were diagnosed with or progressed to stage III NSCLC before durvalumab consolidation. Patients were divided into groups based on the degree of PD-L1 expression: 50% was the only factor that was significantly associated with improved PFS (HR =0.205, P=0.0004) and OS (HR =0.339, P=0.04). CONCLUSIONS: Our study demonstrated that patients whose tumors had >50% PD-L1 expression had significantly longer progression-free survival and overall survival than those with lower PD-L1 expression. This suggests that the degree of tumor PD-L1 expression may play a role in predicting benefit from durvalumab for these patients.

Background Programmed death- ligand 1 (PD-L1) seems to be associated with the immune escape of tumors, and immunotherapy may be a favorable treatment for PD-L1-positive patients. We evaluated intrahepatic cholangiocarcinoma (ICC) specimens for their expression of PD-L1, infiltration of CD8+ T cells, and the relationship between these factors and patient survival. Methods In total, 69 resections of ICC were stained by immunohistochemistry for PD-L1, programmed death factor-1 (PD-1), and CD8+ T cells. CD8+ T-cell densities were analyzed both within tumors and at the tumor-stromal interface. Patient survival was predicted based on the PD-L1 status and CD8+ T-cell density. Results The expression rate of PD-L1 was 12% in cancer cells and 51% in interstitial cells. The expression rate of PD-1 was 30%, and the number of CD8+ T-cells increased with the increase of PD-L1 expression (p Conclusions The expression of PD-L1 in the tumor is related to poor OS, and the number of tumor or interstitial CD8+ T-cells is related to poor OS and DFS. For patients who lose their chance of surgery, PD-L1 immunosuppressive therapy may be the focus of future research as a potential treatment.

Objectives. To compare the clinicopathologic characteristics of urothelial carcinoma (UC), urothelial carcinoma with squamous differentiation (UCSD), and squamous cell carcinoma (SCC) of the bladder, which have been suggested to differ in terms of risk factors, immunophenotype, and prognosis. Methods. We evaluated the clinicopathologic features of radical cystectomy specimens between 1980 and 2015 with a diagnosis of SCC, UCSD, and UC. PD-L1 immunohistochemistry (clinically available clones 22C3, SP142, and SP263) was performed on SCC and UCSD. Multivariate Cox regression was used to identify prognostic factors. Kaplan–Meier curves were plotted to assess cancer-specific survival (CSS). Results. Of the 1478 cases, there were 1126 UC (76%), 217 UCSD (15%), and 135 SCC (9%). Bladder cancer was more common in men than women (80% vs 20%, P pT2) at the time of cystectomy (UCSD-74%, SCC 71%, UC-44%, P

Background: Programmed Death Ligand 1 (PD-L1) is a protein found in tumor cells that could inactivate T-cells. This research was done to identify the characteristics of lung adenocarcinoma patients to PD-L1 expression in Medan. Method: Descriptive research with a cross-sectional design was used and the study was done for 12 months (January – December 2018). Sample’s collection was done at RSUP (Central Public Hospital) H. Adam Malik and the samples diagnosed with lung adenocarcinoma based on histopathological subtyping were sent to the laboratory of Dharmais Jakarta Hospital where the Ventana 22C3 Immunohistochemistry Staining was done. Results: Staining was done in 52 samples at Dharmais Jakarta Hospital and only 35 samples were deemed acceptable. In this study, participants’ ages ranged from 40 to 60 years, where the majority were male patients, 31 (88.6%) and 33 patients (82.5%) were at an advanced stage (III and IV). Conclusion: The study found that the PD-L1 expression was mostly observed in male at the age range of 40 – 60 years and stage IV lung adenocarcinoma patients with Tumour Proportion Score (TPS) of 1 – 49%.

Background Programmed cell death ligand 1 (PD-L1) is a known prognostic and therapeutic marker in malignant tumors. This meta-analysis aimed to investigate the association of PD-L1 expression with the clinicopathological parameters and survival outcomes of gastrointestinal neuroendocrine neoplasms (NENs). Methods PubMed, EMBASE, Web of Science, OVID Medline, the Cochrane Library, and Google Scholar were searched for relevant studies June 30, 2020. Studies reporting PD-L1 immunohistochemistry of gastrointestinal NEN with associated survival data or clinicopathological parameters were included. Results In total, 10 studies were included. Odd ratios (ORs) were combined to evaluate association between PD-L1 expression and clinicopathological parameters. Hazard ratios (HR) and standard errors were combined to evaluate the association between PD-L1 expression and overall survival. PD-L1 expression was significantly associated with higher tumor grade [OR: 3.42; 95% confidence interval (CI): 2.00–5.85, P

Malignant pleural mesothelioma (MPM) is a rare and aggressive tumor, with a poor prognosis. MPM needs to find prognostic factors of survival. We provided the management of patients with MPM and sought to determine whether pre-treatment levels of derived neutrophil-to-lymphocyte ratio (dNLR) as well as PD-L1 expression were reliable prognostic factors of survival. We conducted a single-institution retrospective study, including all patients with MPM treated at La Paz University Hospital between December 2009 and March 2018. Baseline disease, demographics, clinical data, treatment characteristics and complete blood cell counts were collected. We examined dNLR at baseline and data for PD-L1 expression were analyzed in tumor cells by immunohistochemistry. We included 25 patients. The median overall survival (OS) was 15.7 months (95% CI 11.3–20.0). 5 patients had a dNLR greater than 3 (20%). Patients with a dNLR greater than 3 had shorter median OS (8.5 months), than patients with a dNLR less than 3 (17.0 months), with statistically significant differences (p = 0.038). Ten patients (40%) had positive PD-L1 expression (≥ 1%). Patients with positive PD-L1 expression had shorter median OS (8.5 months) than patients with negative PDL1 expression (15.7 months), but without statistically significant association (p = 0.319). The survival data obtained in our sample are consistent with those previously reported. Pretreatment levels of dNLR greater than 3 and positive PD-L1 expression could be significant prognostic factors for poor survival in patients with MPM. Further and prospective studies are needed to explore this relationship and to derive definitive conclusions.

To evaluate the Programmed Cell Death Ligand (PD-L1) expression at diagnosis and relapse in patients with head and neck carcinoma (HNSCC) treated with radio(chemo)therapy. PD-L1 immunohistochemistry was performed in tumor cells (TC) and immune cells (IC) in 44 patients and scored as 0 = 0%, 1 =

Introduction. Immunotherapy has emerged as a potent strategy for treating advanced cancer. This generated new and exciting research, especially regarding tumour microenvironment (TME), including the immune checkpoint system, to further stratify endometrial carcinoma (EC) patients and improve targeted therapy. The objective of the study was to evaluate the TME and PD-L1 impact on various molecular groups. Material and methods. 50 cases of formerly diagnosed ECs were tested for CD4, CD8, CD68 and PD-L1. Results. PD-L1 testing in our group revealed 60% of cases showing

BACKGROUND: Over the past decade, immune checkpoint inhibitors (ICIs) have increasingly become the standard of care for various advanced malignancies, including metastatic clear cell renal cell carcinoma (mccRCC). Most ICIs currently used in clinical practice inhibit the interaction between the programmed cell death protein-1 (PD-1) and programmed death ligand-1 (PD-L1) complex. A deeper understanding of this interaction and PD-L1 expression in tumors has led to more effective therapies in the treatment of advanced cancers, but the debate regarding the utility of PD-L1 as a biomarker continues. OBJECTIVE: We aimed to systematically evaluate the role of PD-L1 in mccRCC in terms of expression and treatment implications. METHODS: Following PRISMA guidelines, we performed a systematic literature search using PubMed and Embase through August 31, 2020. Titles and abstracts were screened to identify articles for full-text review. A hand search was also performed using Google Scholar and the bibliography to relevant studies. RESULTS: A total of 26 articles were identified, and relevant data were extracted and organized. The available information regarding PD-L1 expression in mccRCC from both prospective clinical trials and retrospective studies were summarized. We discussed the utility of PD-L1 as a predictive and prognostic biomarker in mccRCC, its association with other potential biomarkers, and the pattern and level of expression of PD-L1 in primary versus metastatic tumors. CONCLUSIONS: Although significant progress has been made, much more remains to be learned regarding the differences between PD-L1+ and PD-L1- ccRCC tumors, in terms of both the underlying biology and clinical responses to immunotherapy and other agents.

Purpose: Early phase clinical studies are ongoing to evaluate the role of immune checkpoint inhibitors in adenoid cystic carcinoma (ACC) despite a paucity of information on the immune microenvironment. This study aims to better characterize the immune microenvironment of ACC tumours and evaluate survival outcomes based on tumour infiltrating lymphocyte (TIL) and programmed death-ligand 1 (PD-L1) expression. Methods: Patient characteristics, treatment and outcome data were collected for 24 ACC patients. The CD8+(cluster of differentiation 8) TIL and PD-L1 expression were quantified by immunohistochemistry. Marker expression and survival outcomes were evaluated by Kaplan-Meier analysis. Results: All cases were negative for PD-L1 expression; four cases had focal high, eight cases had focal moderate and 12 cases had low TIL expression. Based on TIL expression, there was no difference in disease-free or overall survival. Conclusion: Adenoid cystic carcinoma tumours were found to be associated with a poor immunogenic microenvironment, with absent PD-L1 expression and low CD8+ TILs. There was no association between TIL expression and survival. These data suggest that PD-L1 and TIL expression are unlikely to be useful as predictive biomarkers for response to immunotherapy.

Purpose We aimed to evaluate the feasibility, accuracy, and safety of Programmed Death-1/ Programmed Death-Ligand 1 (PD-1/ PD-L1) expression quantification in cytology cell-block samples obtained through transthoracic CT-guided fine-needle aspiration cytology (FNAC) from the interventional radiologist's perspective. Methods We performed a consecutive unselected series of 361 CT-guided biopsies of pulmonary nodules and masses which came to our observation from June 2017 to October 2018. For each case, exhaustive clinical, morphologic, molecular and tomographic data were available. All the material obtained was fixed in formalin to obtain a cell-block for the pathologist, who performed immunohistochemical analysis to detect PD-L1 expression levels on each sample. Results Of all the analyzed samples, 93.6% (338/361) were defined to be diagnostic, including neoplastic (72%, 260/361) and non-neoplastic lesions (21.6%, 78/361); only 6.4% (23/361) of them resulted in nondiagnostic specimens. Non-small cell lung cancer (NSCLC) accounted for 73.8% of neoplastic lesions (192/260): most of them were adenocarcinoma (83%, 160/192), followed by squamous carcinoma (14%, 27/192) and poorly differentiated carcinoma (3%, 5/192). In 96% of NSCLC (184/192), the diagnosis was reached either in the absence of complications or with early minor complications. PD-L1 expression was evaluated in all 192 NSCLC cytology specimens: 180 immunostainings were found to be adequate for PD-L1 testing. In 76% of cases, PD-L1 expression level was lower than 50%. Conclusion The findings of our study indicate that PD-L1 quantification using a cell-block approach on CT-guided FNAC is a feasible and safe technique and should be taken into account alongside with core biopsy approach, especially in case of advanced disease and/or fragile and older patients.

Immunotherapy for programmed cell death 1 (PD-1) and its ligand, PD-L1, has been considered an effective treatment for ovarian cancer. 18F-labeled fluoro-2-deoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) is a widely used noninvasive imaging tool for diagnosing several cancers. In this study, we investigated the association between PD-L1 expression and the maximum standardized uptake value (SUVmax) using 18F-FDG PET/CT. We retrospectively analyzed clinical data of patients with ovarian cancer who underwent 18F-FDG PET/CT. Patients were categorized into two groups according to PD-L1 expression results. The relationship between clinicopathological characteristics of patients with ovarian cancer and PD-L1 expression was examined. SUVmax was significantly higher in PD-L1-positive tumors than in PD-L1-negative tumors (16.1 ± 5.2 and 12.7 ± 7.0, respectively; p = 0.026). There were no significant differences in age, histologic type, and tumor grade between the PD-L1-negative and PD-L1-positive groups. The receiver operating characteristic curve analysis demonstrated that the highest accuracy (61.8%) for predicting PD-L1 expression was obtained with an SUVmax cutoff value of 10.5. There was a significant correlation between 18F-FDG uptake and PD-L1 expression, suggesting a role of 18F-FDG PET/CT in selecting ovarian cancer candidates for anti-PD-L1 antibody therapy.

The therapeutic potential of immune checkpoint inhibitors is currently being investigated in epithelial ovarian cancer (EOC), but immunological effects of the programmed cell death protein 1 (PD-1)/programmed cell death 1 ligand 1 (PD-L1) axis in EOC still remain poorly understood. The aim of this study was thus to compare infiltration rates of PD-1 and PD-L1 expressing tumor infiltrating leucocytes (TILs) in primary ovarian tumor tissue and metastatic intraperitoneal implants and to investigate its impact on overall survival (OS). Tumor specimens (ovarian tumor tissues and intraperitoneal metastases) of 111 patients were used to investigate the PD-1, PD-L1 and CD8 expression rates on TILs and PD-L1 expression rate of tumor cells. The percentages of CD8, PD-1, and PD-L1 expressing subpopulations of TILs differ in primary ovarian tumor tissues and metastatic intraperitoneal implants. High PD-1 among TILs in peritoneal metastases were associated with favorable OS. High PD-L1 expression in TILs was associated with poor OS. Combining both factors in peritoneal metastases revealed an unfavorable prognosis. Primary ovarian tumor tissue and intraperitoneal metastatic tissues in EOC might have different strategies to evade immune control. Those findings are of importance for the process of biomarker assessment to predict patients’ response to immunotherapy.

Objective: To investigate the immunohistochemical expression of PD-1 and PD-L1 in breast cancer cases and itscorrelation with clinicopathological factors. Study Design: Cross sectional study. Place and Duration of Study: Histopathology department, Armed Forces Institute of Pathology Rawalpindi, form Jan to Jun 2019. Methodology: Sixty five cases of breast cancer were retrieved. Clinicopathological parameters like age, gender,tumor grade and receptor status were noted. Immunohistochemistry for PD-1 and PD-L1 was applied. The datawas entered and statistical analysis was done using SPSS version 21. The associations between variables werefound using the Fisher exact test. Results: Sixty five cases of breast cancer were investigated from tumour registry. The sample included femalepatients, having mean age of 50.86 ± 11.1 Years. Invasive mammary (ductal) carcinoma, NST was the most prevalent subtype 60 (92.3%) and most tumors were grade I/II 53(82%). PD-1 expression was seen in TIL’s 31 (48%) and PD-L1 expression was observed in tumour cells 30 (46%). Expression of PD-1/PD-L1 expression was more common in premenopausal age group and grade I/II tumors. Among molecular subtypes, PD-L1 expression was detected in 11 (52%) TNBC, 5 (71%) in HR-/HER2+ and 12 (32)% in HR + HER2 - and PD-1 expression was observed in 13 (62%) TNBC, 5 (71%) in HR-/HER2+ and 13 (35%) in HR+ HER2-. Conclusion: A large proportion of breast cancer cases show expression of PD-1 / PD-L1. Anti PD-1 and PD-L1therapy may benefit these patients.

Background Immune cells (ICs) infiltration and immune checkpoints have been shown to be important for BC patients’ (pts) prognosis and response to immunotherapy. We aimed to analyze the relation between TILs prevalence and PD-L1 expression with efficacy to an immunostimulatory combination with P and Gem in ABC HER2-negative pts previously treated with ≤4 chemotherapy and/or ≥2 hormone therapy lines from the PANGEA-Breast trial (NCT03025880). Methods Pre-treatment (ttm) metastatic BC samples were assessed for TILs density [% of occupied stromal area upon H&E staining] and for PD-L1 immunohistochemistry expression using monoclonal anti-PD-L1 antibody clone 22C3 (Merck) by calculating ICs score (% of positive infiltrated ICs) and combined positive score [CPS; PD-L1 stained cells (tumor cells, lymphocytes, macrophages) divided by total viable tumor cells, multiplied by 100]. Cut-offs ≥5%, ≥10%, ≥30% were explored for TILs. PD-L1 scores were considered positive if ≥1%. Cut-offs (≥5%, ≥20%, ≥50%) were additionally assessed for PD-L1 as CPS. Logistic regression models were used to evaluate association between TILs density and PD-L1 expression with ttm efficacy in terms of Objective Response Rate [ORR; Complete + Partial Response (CR + PR)], Clinical Benefit Rate [CBR; CR + PR + Stable Disease ≥24 weeks] and Progression Free Survival (PFS), according to RECIST v1.1. Results Thirty-six pts were included, 58% had triple negative BC and 98% ECOG score ≤1. Median number of prior ttm lines was 4. ORR and CBR were 15.2% and 17%, respectively; median PFS was 3.1 months. TILs and PD-L1 were evaluated in 30 and 29 pts, respectively. No association was found between TILs density and ttm efficacy in terms of ORR, CBR and PFS. Analysis of PD-L1 ICs score did not reveal any significant association with ORR, CBR or PFS. However, pts with negative PD-L1 expression by CPS ( Citation Format: Luis De la Cruz, María Gion, Josefina Cruz, Jose Luis Alonso, Vanesa Quiroga, Fernando Moreno, Marta Santisteban, Raquel Andrés, Esther Holgado, Natalia Palazón, Luz Milva Rodríguez, Asunción Soto, Javier Cortés, Alfonso Cortés, Manuel Ramos, Maribel Casas, Massimo Chiesa, Susana Bezares, Rosalía Caballero, Federico Rojo. Association of tumor infiltrating lymphocytes (TILs) density and PD-L1 expression with pembrolizumab (P) plus gemcitabine (Gem) efficacy in patients with HER2-negative advanced breast cancer (ABC) from the GEICAM/2015-04 (PANGEA-Breast) study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS4-38.

Objectives Pembrolizumab is recommended for patients with previously untreated non-small cell lung cancer (NSCLC) with a programmed death ligand 1 (PD-L1) tumor proportion score (TPS) of ≥1%. The KEYNOTE-024 study described the efficacy of pembrolizumab in patients with previously untreated NSCLC who had a PD-L1 TPS of at least 50 %. However, patients with untreated brain metastasis (BM) were excluded from many clinical trials. Therefore, we assessed the efficacy of pembrolizumab against BM of NSCLC with high tumor PD-L1 expression. Materials and Methods We retrospectively reviewed patients who received pembrolizumab as first-line treatment against NSCLC with PD-L1 TPS ≥ 50 % between March 2017 and September 2019. Treatment efficacy was compared between patients with (BM group) and without BM (non-BM group). In addition, the BM group was divided into patients who previously received treatment for BM before pembrolizumab (BM-T group) and those with no prior treatment for BM (BM-not T group). Results Eighty-seven patients (23 BM group and 64 non-BM group) were assessable for efficacy. No significant differences in patient characteristics were found between the BM and non-BM groups, but proportion of patients with stage IV at diagnosis was significantly higher in the BM group. Median progression-free survival (PFS) (6.5 months vs. 7.0 months) and overall survival (OS) (21.6 months vs. 24.6 months) did not significantly differ between the two groups. The response rate of BM was 70 %. The BM group was subdivided into 13 patients in the BM-T group and 10 patients in the BM-not T group. No significant differences in patient characteristics were found between the two groups, but maximum diameter of BM and proportion of patients with symptomatic BM were significantly greater in the BM-T group. PFS and OS did not significantly differ between the two groups. The median PFS of BM was 13.6 months in the BM-T group and 18.6 months in the BM-not T group. Conclusion Pembrolizumab may be effective for BM caused by previously untreated NSCLC with high PD-L1 tumor expression.

Purpose: Intrapatient heterogeneity of programmed death ligand 1 (PD-L1) expression and tumor mutational burden (TMB) in gastroesophageal adenocarcinoma (GEA) could influence their roles as predictive biomarkers for response to immune checkpoint inhibitors (ICI). In this retrospective analysis, we evaluated the spatiotemporal heterogeneity and prognostic relevance of PD-L1 expression and TMB in GEA. Experimental Design: A cohort of 211 patients with stage II–IV GEA was retrospectively reviewed for a total of 407 tumor samples with PD-L1 expression data and 319 tumor samples with TMB data. PD-L1 status was defined as positive if combined positive score (CPS) ≥1 using the 22C3 pharmDx assay. TMB levels were categorized as low, intermediate, or high (≤5, 5–15, or >15 mutations/Mb), or using a single threshold ( Results: Of 407 tumors, 56% were PD-L1 negative and 44% PD-L1 positive. Of 319 tumors, 50% were TMB-low, 45% TMB-intermediate, and 5% TMB-high; 86% had Conclusions: PD-L1 expression and TMB exhibit marked spatial and temporal heterogeneity in GEA. This heterogeneity should be considered when obtaining tumor samples for molecular testing and when deciding whether ICI therapy is appropriate. See related commentary by Klempner et al., p. 6401

BACKGROUND CD155 is an immune checkpoint protein in cancers and interacts with ligands to regulate the immune microenvironment. The expression of CD155 is correlated with the prognosis and pathological features of breast cancer. AIM To investigate the expression status of CD155 and the association with exhausted CD4+ helper and CD8+ cytotoxic tumor infiltrating lymphocytes (TILs) and PD-L1 in the breast cancer microenvironment. METHODS One hundred and twenty-six breast cancer patients with invasive ductal breast cancer were consecutively recruited into this study. Immunohistochemistry was used to detect the expression CD155, PD-L1 and PD-1 on tumor-infiltrating immune cells and tumor cells in the microenvironment. RESULTS The proportion of patients with CD155 expression was higher in triple negative breast cancer (72.7%) than in Luminal A patients (22.2%, P < 0.05). Patients with positive CD155 expression had a higher percentage of CD4+/PD-1+ helper TILs (30%) than patients with negative CD155 expression (21%, P < 0.05). Patients with positive CD155 expression also had higher cell counts of exhausted CD4+ TILs [47 vs 20/high-power fields (HPF)] and unexhausted CD8+ TILs (30 vs 17/HPF) than patients with negative expression (P < 0.05). CD155 expression was correlated with increased PD-L1 expression in immune cells, 0.8% and 0.02% immune cells expressed PD-L1 in patients with positive and negative CD155 expression, respectively (P < 0.05). CONCLUSION CD155 was related to an inhibitory immune breast cancer microenvironment. CD155 was associated with a high proportion of exhausted CD4+ and unexhausted CD8+ TILs and high PD-L1 expression in immune cells.

Introduction We analyzed the prevalence of non–small-cell lung cancer (NSCLC) with a programmed cell death ligand 1 (PD-L1) tumor proportion score (TPS) of ≥ 50% and compared the results with the existing data from clinical trials and databases from other countries. Materials and Methods The Latin American Cooperative Oncology Group and Grupo Brasileiro de Oncologia Toracica performed a retrospective, cross-sectional study from August 2017 to April 2018. PD-L1 expression was collected from pathology reports from 5 laboratories in Brazil. All tests were sponsored by the pharmaceutical industry on request from the treating medical oncologist. PD-L1 expression was assessed by immunohistochemistry. The variables were summarized as absolute and relative frequencies or the median and interquartile range. Pearson's χ2 test was used to compare the TPS categories stratified by sex, age, and histologic type. All analyses were performed with SAS, version 9.4, and were deemed statistically significant at P Results A total of 1512 patients were included in the present study. Their median age was 66 years. Most patients were men (56.02%), and the most common histologic type was adenocarcinoma (58.04%); 109 tumors (11.31%) had EGFR mutations and 34 (3.64%) had ALK gene rearrangements. Overall, 56.54% had a PD-L1 TPS Conclusion The prevalence of high PD-L1 expression among the Brazilian NSCLC samples was lower than previously described in other countries, which could affect the number of patients who might be candidates for immunotherapy alone.

Background Kaposi sarcoma (KS) is a mesenchymal tumor with distinct histopathological features according to tumor progression. Programmed death-1 (PD-1) and its ligand PD-L1 play major roles in the immune escape strategy of tumors. Objectives This study evaluated expression of PD-1 and PD-L1 in various stages of KS and investigated associations between their expression and clinical characteristics. Methods Fifty cases with histopathologically diagnosed KS were classified as early or late stage. These specimens were stained with anti-PD-1 and anti-PD-L1 antibodies. The extent of expression in the intratumoral and peri-tumoral areas was judged by two dermatopathologists. Results PD-1 and PD-L1 were expressed in 72.2% (13/18) and 11.1% (2/18) of early-stage cases, respectively, compared with 43.8% (14/32) and 28.1% (9/32) of late-stage cases, respectively. At the late stage, PD-1 expression was significantly higher in the peri-tumoral area than in the intratumoral area (P = 0.001). PD-1 expression in the intratumoral area was significantly higher at the early stage than at the late stage (P = 0.013). PD-L1 expression in the peri-tumoral area was significantly higher at the late stage than at the early stage (P = 0.038). Conclusions The pattern of PD-1 and PD-L1 expression differs according to the stage of KS, but is unaffected by clinical variables.

Pembrolizumab is the standard first‐line treatment for advanced non‐small cell lung cancer (NSCLC) with programmed death‐ligand 1 (PD‐L1) expression tumor proportion score (TPS) ≥50%. The benefit of pembrolizumab in patients with advanced NSCLC and poor performance status (PS ≥3) is limited, even when the tumor is PD‐L1‐expression‐positive. We retrospectively reviewed a total of four NSCLC cases with high PD‐L1 expression (TPS ≥50%) and poor PS. The only patient with very high PD‐L1 expression (TPS 100%) responded to pembrolizumab, but none of the three patients with high PD‐L1 expression (50%–80%) responded to pembrolizumab. In conclusion, pembrolizumab can serve as a treatment option for patients with poor PS, if PD‐L1 expression TPS is 100%., Pembrolizumab may be a treatment option in patients with poor PS, if TPS of PD‐L1 on tumor cells are 100%.

Intra-tumor heterogeneity for PD-L1 expression in non-small cell lung cancer (NSCLC) might lead to inaccurate stratification of patients to immunotherapy. The purpose of this research was to quantitate the effect of different factors on the risk of inaccurate diagnosis of PD-L1 expression.MATLAB software was used to model tumor with a different fraction, distribution and clustering of PD-L1 protein expression and their effect on false positive and negative diagnosis in subsets of the modeled tumor (representing biopsies). Additionally, we evaluated the agreement between PD-L1 status in random segments and whole slides of PD-L1 stained clinical NSCLC cases.Our computer-based model showed a significant increase in error rate when the fraction of PD-L1 positive cells was closer to the cut-off value (error rate of 33.33 %, 0.45 % and 0.74 % for PD-L1 positivity in 40-60%, ≤20 % and ≥80 % of tumor cells, respectively, P 0.0001). In addition, biopsy size showed negative correlation with error rate (P 0.0001) and larger clusters of PD-L1 positive cells were associated with higher error rate (P 0.0001). Analysis of the clinical samples supported those of the computer-based model with higher error rate in cases with positive PD-L1 expression closer to the cutoff value. Based on our computerized model and clinical analysis, we developed a model to predict error rate based on biopsy size and the fraction of PD-L1 positive cells in the biopsy.Analysis of small biopsies for PD-L1 expression might be associated with significant error rate. The model presented can be used to identify cases with increased risk for error in whom interpretation of the test results should be made with caution.

Objectives: Programmed Cell Death Ligand1 (PD-L1) tissue expression in CRC (colorectal cancer) displays conflicting results among various studies. We aimed to identify the rate of PD-L1 positivity in colorectal carcinoma, and it's immune infiltrating cells, their relationship with clinicopathologic parameters of patients, and to correlate the results with other studies. Methods: PD-L1 antibody retrospectively analyzed immunohistochemically in tissue microarray blocks of 99 specimens with colonic and rectal carcinomas operated between January 2015 to December 2017. A comparison performed between PD-L1 expression in tumor cells (TCs) as well as tumor-infiltrating immune cells (TIICs) for age, sex, histological differentiation, the primary tumor location, number of involved lymph nodes, angiolymphatic invasion, and TNM stage. Results: Of the 99 patients, the median age was 54.5 (range: 18 to 83) years. Fourteen samples were PD-L1 positive in TCs, increased to 32% in TIICs. A significant expression of PD-L1in TCs was correlated with medullary histology (p= 0.03), number of the involved lymph nodes (p= 0.02), distant metastasis (p= 0.001), and TNM stage (p= 0.0001). The PD-L1 status in TIICs was again connected with adverse clinical and pathological parameters. Conclusions: The expression of PD-L1 in TCs and TIICs is associated significantly with advanced cancer or lymphatic invasion in patients who underwent surgery after a diagnosis of CRC. The research designates the significance of estimation of TCs and TIICs in correlation to clinicopathologic characteristics of patients a finding that could produce a piece of evidence for precise electing immunotherapy.

Background Studies concerning programmed death-ligand 1 (PD-L1) expression in precancerous lesions of head and neck (HN) region have shown variable results. Methods We systematically reviewed the published evidence on PD-L1 expression in HN precancerous lesions. Results Of 1058 original articles, 14 were included in systematic review and 9 in meta-analysis. The pooled estimate of PD-L1 expression was 48.25% (confidence interval [CI] 21.07-75.98, I2 98%, tau2 0.18). PD-L1 expression appeared to be more frequent in precancerous lesions than in normal mucosa (risk ratio [RR] 1.65, CI 0.65-4.03, I2 91%, tau2 0.82) and less frequent than in invasive squamous cell carcinoma (RR 0.68, CI 0.43-1.08, I2 91%, tau2 0.22). Conclusions PD-L1 expression could reflect a point of balance between host immune response and cancer escape ability. High heterogeneity and moderate quality suggest that further studies with larger sample size and more rigorous case selection will allow more precise assessment of PD-L1 expression in HN precancerous lesions.

Immunotherapies targeting the PD-1/PD-L1 pathway have shown some success in cervical and vulvar squamous cell carcinomas, but little is known about the potential vulnerability of these tumors to other checkpoint inhibitors. TIM-3 is a checkpoint molecule that exerts immunosuppressive function via its interaction with Gal-9. TIM-3 and Gal-9 have been identified on a variety of malignancies but have not been studied in cervical and vulvar cancers, nor has their relationship to PD-L1 been established. Sixty-three cervical and vulvar invasive (n = 34) and intraepithelial lesions (n = 29) were assessed for TIM-3, Gal-9, and PD-L1 in tumor/lesional cells and associated immune cells. Tumoral TIM-3 expression was identified in 85% of squamous cell carcinomas but only 21% of intraepithelial lesions (p

Background: The immune checkpoint ligand, programmed cell death 1 ligand 1 (PD-L1), is expressed in various tumors and associated with response to drugs that target programmed cell death protein 1. Previous studies have estimated the level of PD-L1 expression among different stages of thymoma and thymic carcinoma to evaluate its potential use as a diagnostic factor; however, its varying expression level has been problematic. We conducted this meta-analysis of published literature to evaluate PD-L1 expression in thymomas and thymic carcinomas. Methods: We analyzed 12 studies that included 320 patients with type A/AB/B1 thymoma, 225 patients with type B2/B3 thymoma, and 180 patients with thymic carcinoma. Results: No difference in PD-L1 expression level was found between the B2/B3 vs C groups (odds ratio [OR], 0.67; 95% confidence interval [CI], 0.26, 1.76; p = 0.42). However, the heterogeneity was very high ( I2 = 78%), and a significant difference was found between groups A/AB/B1 and B2/B3 (OR, 0.22; 95% CI, 0.12, 0.41; p < 0.001), with a relatively low heterogeneity ( I2 = 55%). Conclusion: PD-L1 positivity might be a useful factor to differentiate type A/AB/B1 thymoma from type B2/B3 and thymic carcinoma. This result might be valuable for potential anti PD-L1 treatment in thymoma and thymic carcinoma.

BACKGROUND: PD-L1 expression is the only FDA-approved biomarker for immune checkpoint inhibitors (ICIs) in patients with lung adenocarcinoma, but sensitivity is modest. Understanding the impact of molecular phenotype, clinical characteristics, and tumor features on PD-L1 expression is largely unknown and may improve prediction of response to ICI. METHODS: We evaluated patients with lung adenocarcinoma in whom PD-L1 testing and targeted next-generation sequencing (MSK-IMPACT) was performed on the same tissue. Clinical and molecular features were compared across PD-L1 subgroups to examine how molecular phenotype associated with tumor PD-L1 expression. In patients treated with anti-PD-(L)1 blockade, we assessed how these interactions impacted efficacy. RESULTS: 1586 patients with lung adenocarcinoma had paired PD-L1 testing and targeted next-generation sequencing. PD-L1 negativity was more common in primary compared to metastatic samples (p

Background Penile squamous cell carcinoma (PSCC) bears poor prognosis due to its rarity and limited treatment options, especially after failure of standard treatments. Effective therapeutic options were desperately needed. Case Presentation We report a recurrent metastatic PSCC patient with positive programmed death ligand 1 (PD-L1) expression (≥10%) and tumor mutation burden (TMB) of 8.87 (Muts/Mb) who obtained significant response to immunotherapy, with progression-free survival (PFS) exceeding 10 months. Conclusion This is the first case presenting remarkable response to immunotherapy in a Chinese PSCC patient. The remarkable response might be associated with PD-L1 expression, indicating that PD-L1 expression could be a promising biomarker for immunotherapy in PSCC. TMB ranking may also contribute to patient selection. However, large clinical trials are needed to validate these notions.

Background: To determine the frequency of discordance in programmed death-ligand 1(PD-L1) expression between primary tumors and paired distant metastases in advanced cancers. Methods: We searched MEDLINE and EMBASE for eligible studies and assessed their methodologic quality using QUADAS-2 tool. We estimated the discordant rates (positive to negative or vice versa) of PD-L1 expression in primary tumors and paired distant metastases using logistic-normal random effects model. We performed subgroup analyses based on the PD-L1 status of primary tumors (positive or negative), location of primary tumors (lung or others) and distant metastases (central nervous system or others), timing of distant metastases (synchronous or metachronous), positivity thresholds of PD-L1 expression (1% or 5%) and types of antibody clones used (E1L3N or SP142). Results: Thirteen eligible studies including 451 cases were identified. The included studies were judged to have low to unclear risk of bias. The pooled estimate of discordant rates in PD-L1 expression was 31% (95% CI= 19–47%), with high heterogeneity across the studies (I2 = 75%). There was no significant effect modification in the discordant rates according to the predefined subgroups. Conclusion: Approximately one-third of advanced cancer cases have discordance in PD-L1 expression between primary tumors and paired distant metastases. A more liberal testing of PD-L1 expression in both primary and metastatic tumors is recommended in order to identify patients who may benefit from immune checkpoint blockade treatment. Further research exploring the mechanisms and its impact are warranted.

The PD-1/PD-L1 pathway plays a critical role in the physiologic inhibition and modulation of the immune response in normal tissue. Many tumors evade immune detection and response by upregulating PD-L1 expression. Humanized monoclonal PD-1 and PD-L1 antibodies have proven as both tolerable and effective treatment in many neoplasms. Extramammary Paget disease (EMPD) is a deformative and debilitating cutaneous malignancy in which definitive treatment options are limited with high recurrence rates after surgical excision. To the best of our knowledge, there is little published information regarding EMPD and PD-L1 expression. We evaluated 18 EMPD surgical pathology cases for tumor cell and tumor-associated inflammatory (TAI) cell PD-L1 expression. We identified PD-L1 tumor cell expression in 3 (17%) of the cases: 2 of 4 invasive cases (50%) and 1 of 14 (7%) noninvasive cases. One invasive case had lymph nodal metastasis with PD-L1 tumor cell expression. The host inflammatory response intensity and PD-L1 expression were variable in cases negative for tumor cell PD-L1 expression; however, a marked inflammatory response and TAI PD-L1 expression were present in all cases positive for tumor cell PD-L1 expression. In conclusion, 1 in 14 (7%) in situ EMPD cases showed tumor cell PD-L1 expression and 2 of 4 invasive cases (50%) showed tumor cell PD-L1 expression. TAI cells were more often positive (83%) than tumor cells (17%) for PD-L1 expression.

The programmed cell death 1 (PD-1) pathway is a recently recognized mechanism of tumor immune evasion. In this study, programmed cell death ligand 1 (PD-L1) expression was evaluated in 95 patients with systemic anaplastic large cell lymphoma: 45 ALK+ and 50 ALK-. ALK+ anaplastic large cell lymphoma was more often positive for PD-L1 than ALK- anaplastic large cell lymphoma (76% vs 42%, p = 0.002). ALK- anaplastic large cell lymphoma showed a strong correlation between PD-L1 expression and STAT3 activation (measured by pSTAT3Tyr705) (r = 0.8, p 0.05). Negative ALK status and high IPI score (≥3) were associated with shorter overall survival (p = 0.009 and p = 0.0005, respectively). Overall survival was not different between patients with PD-L1+ vs PD-L1- anaplastic large cell lymphoma (p = 0.44), regardless of ALK status and International Prognostic Index (IPI) score. We conclude that PD-L1 expression is more common in ALK+ anaplastic large cell lymphoma than ALK- anaplastic large cell lymphoma. In ALK- anaplastic large cell lymphoma, PD-L1 is strongly correlated with STAT3 activation and is associated with more frequent EMA and less frequent CD2 expression. PD-L1 has no prognostic significance in predicting the outcome of patients with systemic anaplastic large cell lymphoma, regardless of ALK status. PD-L1 expression on the anaplastic large cell lymphoma cells suggests these patients as potential candidates for PD-1 blockade immunotherapy.

Background: Immune checkpoint inhibitors (ICIs) are standard therapies for patients with advanced non-small-cell lung cancer (NSCLC) and a programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) ≥50%. Tumor mutation burden (TMB) also predicts response to ICIs but is often not available in real time for decision making in the first-line setting. Smoking exposure can be a proxy for TMB in NSCLC. The impact of smoking status on efficacy of PD-1 blockade in NSCLC patients with PD-L1 TPS ≥50% has not been well defined. Patients and methods: To investigate the relationship between smoking and activity of ICIs in NSCLC, we retrospectively studied 315 patients with NSCLC and PD-L1 TPS ≥50% at five USA academic medical centers. Objective response rates (ORRs), progression-free survival (PFS), and duration of response (DOR) were compared between never (10 pack-years) smokers. A subset of patients underwent next-generation sequencing to estimate TMB. Results: We identified 36 (11%) never, 42 (13%) light, and 237 (75%) heavy smokers with NSCLC and PD-L1 TPS ≥50% treated with ICIs. Objective responses were observed in 27%, 40%, and 40% of never, light, and heavy smokers, respectively (P = 0.180 never versus heavy; P = 1.000 light versus heavy). Median PFS and median DOR were numerically shorter in never and light smokers compared with heavy smokers (PFS 3.0 versus 4.0 versus 5.4 months; median DOR 6.9 versus 10.8 versus 17.8 months), but were not statistically different [PFS: hazard ratio (HR) 1.37, P = 0.135 and HR 1.24, P = 0.272; DOR: HR 1.92, P = 0.217 and HR 1.79, P = 0.141]. Conclusions: PD-(L)1 inhibitors are associated with antitumor activity in NSCLC with PD-L1 TPS ≥50% regardless of smoking status. Nevertheless, there is a signal of potentially decreased durability among never and light smokers that should be further evaluated. Distinct immunobiologic features may affect initial response versus durability of antitumor immunity to programmed cell death 1 (PD-1) blockade.

tumor-infiltrating immune cells are present in GIST and seem to be associated with disease outcomes and also with increasing the activity of imatinib”

Recent research revealed that doxorubicin (DOX) decreased expression of programmed death-ligand 1 (PD-L1) in cancer cells. However, the detailed mechanisms underlying this effect are not well established. Here, we demonstrate that doxorubicin down-regulates PD-L1 expression through induction of AU-rich element (ARE) binding protein tristetraprolin (TTP) in cancer cells. PD-L1 mRNA contain three AREs within its 3'UTR. Doxorubicin induced expression of TTP, increased TTP binding to the 3rd ARE of the PD-L1 3'UTR, and increased decay of PD-L1 mRNA. Inhibition of TTP abrogates the inhibitory effect of doxorubicin on PD-L1 expression. Our data suggest that TTP plays a key role in doxorubicin-mediated down-regulation of PD-L1 by enhancing degradation of PD-L1 mRNA in cancer cells.

Rationale and Objectives To explore the potential value of radiomic features-derived approach in assessing PD-L1 expression status in nonsmall cell lung cancer (NSCLC) patients. Materials and Methods A cohort of 399 stage I–IV NSCLC patients were enrolled. Tumor segmentation was performed to select essential primary lesions of NSCLC cases after PET/CT images acquisition. Features were extracted, then filtered with automatic relevance determination and minimized with LASSO model based on its relevance of PD-L1 expression status. Finally, we built predictive models with features from the CT, the PET, and the PET/CT images, respectively, for differentiating different status of specific PD-L1 types. Five-fold cross validation was practiced to evaluate the signatures’ accuracy, and the receiver operating characteristic as well as the corresponding area under the curve (AUC) was reckoned for each model. Results With the total of 24 selected features which were significantly associated with PD-L1 expression levels, models based on CT-, PET-, PET/CT-derived features were built and compared. For PD-L1 (SP142) expression level over 1% prediction, models that comprised radiomic features from the CT, the PET, and the PET/CT images resulted in an AUC of 0.97, 0.61, and 0.97, respectively; models for over 50% prediction resulted with AUC of 0.80, 0.65, and 0.77. For PD-L1 (28-8) expression level prediction, predictive models of over 1% expression scored at 0.86, 0.62, and 0.85; and signatures of over 50% expression reached the score of AUCs at 0.91, 0.75, and 0.88, respectively. Conclusion The radiomic-based predictive approach, especially CT-derived predictive model, may anticipate PD-L1 expression status in NSCLC patients relatively accurate. It may be helpful in guiding immunotherapy in clinical practice and deserves further analysis.

The role of immune-related adverse events (irAEs), as a surrogate predictor of the efficacy of checkpoint inhibitors, has not yet been described in the setting of first-line, single-agent pembrolizumab for patients with metastatic non-small-cell lung-cancer (NSCLC) with a programmed death-ligand 1 (PD-L1) expression of ≥ 50%.We previously conducted a multicenter retrospective analysis in patients with treatment-naive metastatic NSCLC and a PD-L1 expression of ≥ 50% receiving first-line pembrolizumab. Here, we report the results of the irAE analysis and the potential correlation between irAEs and clinical outcomes.A total of 1010 patients were included in this analysis; after a 6-week landmark selection, 877 (86.8%) patients were included in the efficacy analysis. Any grade irAEs (P .0001), grade 3/4 irAEs (P = .0025), leading to discontinuation irAEs (P = .0144), multiple-site and single-site irAEs (P .0001), cutaneous irAEs (P = .0001), endocrine irAEs (P = .0227), pulmonary irAEs (P = .0479), and rheumatologic irAEs (P = .0018) were significantly related to a higher objective response rate. Any grade irAEs (P .0001), single-site irAEs (P .0001), multiple-site irAEs (P = .0005), cutaneous irAEs (P = .0042), endocrine irAEs (P .0001), gastrointestinal irAEs (P = .0391), and rheumatologic irAEs (P = .0086) were significantly related to progression-free survival. Any grade irAEs (P .0001), single-site irAEs (P .0001), multiple-site irAEs (P = .0003), cutaneous irAEs (P = .0002), endocrine irAEs (P = .0001), and rheumatologic irAEs (P = .0214) were significantly related to overall survival.This study confirms the feasibility and the safety of first-line, single-agent pembrolizumab, in a large, real-world cohort of patients with NSCLC with PD-L1 expression ≥ 50%. The occurrence of irAEs may be a surrogate of clinical activity and improved outcomes in this setting.