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Triple-negative breast cancer (TNBC) accounts for 15-20% of all breast carcinomas and represents an aggressive variant with a high mortality rate. PD-L1 is a protein that plays a pivotal role in suppressing the adaptive immune system. It has become a central target of the immunotherapy approach. Determining the PD-L1 status can identify TNBC patients who may benefit from targeted therapy. This study was performed to estimate the prevalence of PD-L1 expression among Polish TNBC patients. A total of 123 patients with TNBC were tested for PD-L1 expression using immunohistochemical studies. The PD-L1-positive tumors were found in 55 patients (45%), while PD-L1-negative tumors were found in 68 patients (55%). The PD-L1 positive tumors included 17 patients (31%) with the expression covering up to 1% of tumor area, 23 patients (42%) covering 2-5%, 8 patients (14%) covering 6-10% and 7 patients (13%) covering more than 10% of tumor area. The PD-L1 negative tumors included 17 patients (25%) with the expression covering less than 1% of tumor area and 51 patients (75%) with a complete lack of expression. There were no significant differences between the groups with different status of PD-L1 and the clinical tumor and lymph node stages as well as the patients’ age.

Despite the well-established pathogenic effect of high-risk human papillomavirus (hrHPV) genotypes on endocervical adenocarcinomas (ECAs), the prognostic values of hrHPV genotypes and their association with other prognostic variables have not been established. We categorized 120 usual-type human papillomavirus-associated (HPVA) ECA cases into 3 species groups (HPV16+, HPV18/45+, and other genotypes+) based on the hrHPV status. The clinical-stage, invasion patterns (Silva), and programmed death ligand-1 (PD-L1) expression were compared among genotype groups. In addition, log-rank test and Kaplan-Meier survival curves were used to compare progression-free survival (PFS) among different patient groups. A total of 120 ECA cases with positive hrHPV tests were included in this study. Among them, 51 (42.5%) were positive for HPV16, 50 (41.7%) were positive for HPV18 or 18/45, 9 (7.5%) were positive for other hrHPV genotypes (not including HPV16/18/45). Our data showed patients had no significant difference in clinical stages (P=0.51), invasion patterns (P=0.55), and PFS (P=0.59) across genotype groups. Overall, a relatively high prevalence of PD-L1 expression was observed in HPVA ECAs (25% by tumor proportion score [TPS] and 55% by a combined positive score [CPS]). Using TPS, 19.6% (10/51) HPV16+ cases, 32.0% (16/50) cases of HPV18 or 18/45+ cases, and 22.2% (2/9) cases of other genotypes+ cases demonstrated PD-L1 positivity. No significant difference in PD-L1 expression was seen across genotype groups (P=0.35). PD-L1 expression in tumors with patterns B and C was significantly higher than in those with pattern A (P=0.00002). Patients with PD-L1-positive tumors by either CPS or TPS showed significantly poorer PFS than those with PD-L1-negative tumors (CPS, P=0.025; TPS, P=0.001). Our data support that HPV genotypes have no prognostic value in HPVA ECAs, while PD-L1 expression serves as a negative prognostic marker in HPVA ECAs and implies an unfavorable outcome.

OBJECTIVE: The interaction between programmed cell death protein 1 (PD-1) on activated T-lymphocytes and programmed death-ligand 1 (PD-L1) on tumor cells or antigen-presenting cells sends immunosuppressive signals leading to the escape of tumor cells from the host anti-tumor immune response. Inhibiting this interaction with antibodies against PD-1 or PD-L1 is emerging as a valuable therapeutic strategy. However, tissue distribution patterns for PD-L1 and PD-1 in breast cancer patients from India are not reported, yet many clinical trials are underway. In this study the expression of PD-1 and PD-L1 in breast cancer patient samples from India was characterized. MATERIALS AND METHODS: The study included 392 cases of operated breast cancer (2012–2017) from a tertiary cancer care center in Bangalore, Karnataka, India. Paraffin blocks were retrievable and receptor status was known. Immunohistochemistry (IHC) was performed using anti-PD-L1 and anti-PD-1 antibodies. RNA was isolated from 76 fresh tumors and nine adjacent normal tissues (2019). PD-L1 transcript levels were measured by RT-qPCR using Hypoxanthine-guanine phosphoribosyl transferase (HPRT) as a reference gene. RESULTS: Based on IHC, PD-1 expression within tumor-infiltrating immune cells (TIICs) was observed in 55/385 cases (14%) across all breast cancer types. In triple-negative breast cancer (TNBC), 21/132 cases (16%) showed PD-1 staining in TIICs. The overall expression of PD-L1 in breast tumor cells across all breast cancer subtypes and TIICs was 11% (41/378) and 39% (151/385), respectively. A relatively higher proportion of TNBC cases had PD-L1 expression in tumor cells (17/132 cases, 13%) and immune cells (68/132 cases, 52%). We also detected PD-L1 transcript expression by qRT-PCR in freshly isolated tumor samples. CONCLUSION: These findings show that around 52% (68/132) of the TNBC cases express PD-L1 in TIICs. Hence, anti-PD-1/PD-L1 therapy alone or combined with chemotherapy may be a promising treatment for TNBC in Indian patients.

Purpose To explore CT radiomics for predicting programmed cell death ligand 1 on tumor cells (PD-L1) status in gastric cancer (GC).Methods From March 2019 to July 2020, 358 patients identified with GC who underwent surgery at our hospital were enrolled in this study retrospectively. All patients were divided into primary (n=239) and validation (n=119) cohorts based on the time of surgery at a ratio of 3:1. Radiomic features were extracted from regions of interest manually drawn on venous CT images. Besides, preoperative tumor markers of all patients were collected and analyzed. The signatures based on radiomics were built using Support Vector Machine (SVM) and Random Forest (RF). Receiver operating characteristic (ROC) curve was performed to assess diagnostic efficiency. Decision curve analysis confirmed the clinical utility.Results Numerous radiomic features (all pConclusion It was promising to predict PD-L1 status in GCs noninvasively using CT radiomics. It might help to improve clinical decision making with regard to immunotherapy.

BackgroundImmunotherapy is an important treatment for triple-negative breast cancer (TNBC). The programmed death ligand 1 (PD-L1) is a pivotal biomarker in TNBC, and its expression is closely related to immunotherapy response. Therefore, the association of p53 expression and mutation and PD-L1 expression was explored. Methods and Results PD-L1 expression and p53 mutation and expression were evaluated by immunohistochemistry. PD-L1 expression and expression levels between p53 mutation (missense and nonsense) and wild type; no-expression/loss vs. expression; and missense vs. nonsense groups were compared. PD-L1 expression was found mainly in tumor-infiltrating immune cells (ICs) in TNBC. Positive PD-L1 expression was associated with a high Ki67 index. There was a significant association between p53 mutation, especially missense mutation and higher histological grade, and PD-L1 expression in ICs. Compared with p53 nonsense mutation, cases with missense mutations tended to display more PD-L1 positive ICs. However, PD-L1 expression in ICs was not significantly different between the p53 mutation and expression groups. Conclusionsp53 missense mutation is partially involved in the regulatory expression of PD-L1. Both p53 missense mutation and PD-L1 expression may be potential targets for improving immunotherapy response in TNBC.

BackgroundAt present, the prognostic significance of programmed cell death receptor ligand 1 (PD-L1) expression in oropharyngeal squamous cell carcinoma (OPSCC) patients is still controversial. In this study, we aim to synthesize relevant studies that have assessed the prognostic value of PD-L1 in patients with primary OPSCC treated according to the current standard-of-care.MethodsA systematic search of Medline/PubMed, Cochrane, Embase, Web of Science, and Scopus was conducted to define the prognostic role of PD-L1 expression in OPSCC. All studies published before July 31, 2021 were screened. Summary hazard ratios (sHR) with 95% confidence intervals (CIs) were calculated using a random-effects model.ResultsA total of 1522 OPSCC patients from 12 studies were included. PD-L1 expression in OPSCC tumor cells (TCs) was significantly associated with longer overall survival (sHR=0.63, 95% CI 0.50-0.79), and progression-free survival (sHR=0.62, 95% CI 0.49-0.79). A benefit in survival was also observed in PD-L1-positive OPSCC patients who underwent surgery (sHR=0.34, 95% CI 0.18-0.65). Finally, although PD-L1-positive expression was related to better outcomes both in HPV-negative and HPV-positive OPSCC, the difference reached the statistical significance only in the HPV-positive subgroup (sHR=0.37, 95% CI 0.19-0.73). No heterogeneity emerged between studies for all considered outcomes, with I2 ranging from 0% for progression-free survival to 11% for overall survival.ConclusionsPD-L1 expression on TCs associated with improved survival in OPSCC. In particular, HPV-positive OPSCC most benefited from PD-L1 expression when compared to the PD-L1 negative counterpart. Thus, PD-L1 might represent a useful biomarker to stratify prognosis in OPSCC in addition to HPV status.

To assess if quantitative integrated deep learning and radiomics features can predict the PD-L1 expression level in preoperative MRI of hepatocellular carcinoma (HCC) patients. The data in this study consist of 103 hepatocellular carcinoma patients who received immunotherapy in a single center. These patients were divided into a high PD-L1 expression group (30 patients) and a low PD-L1 expression group (73 patients). Both radiomics and deep learning features were extracted from their MRI sequence of T2-WI, which were merged into an integrative feature space for machine learning for the prediction of PD-L1 expression. The five-fold cross-validation was adopted to validate the performance of the model, while the AUC was used to assess the predictive ability of the model. Based on the five-fold cross-validation, the integrated model achieved the best prediction performance, with an AUC score of 0.897 ± 0.084, followed by the deep learning-based model with an AUC of 0.852 ± 0.043 then the radiomics-based model with AUC of 0.794 ± 0.035. The feature set integrating radiomics and deep learning features is more effective in predicting PD-L1 expression level than only one feature type. The integrated model can achieve fast and accurate prediction of PD-L1 expression status in preoperative MRI of HCC patients.

Background/aim Treatments containing ipilimumab have shown a good outcome in patients with non-small cell lung cancer (NSCLC) regardless of the PD-L1 tumor proportion score (TPS). However, the association between PD-L1 TPS and the expression of CTLA-4 in tumor-infiltrating lymphocytes is unknown. Patients and methods Fifty-five NSCLC patients who underwent surgery in our hospital were included in this study. We measured the proportions of CTLA-4+ regulatory T cells, and CTLA-4+ CD8 T cells, and statistically analyzed their correlations with the PD-L1 TPS. Results Statistical correlations were found neither between the proportion of CTLA-4+ regulatory T cells to CD8 T cells and the PD-L1 TPS (p=0.2859) nor between the proportion of CTLA-4+ cells in CD8 T cells and the PD-L1 TPS (p=0.1919). Conclusion The proportions of CTLA-4+ regulatory T cells to CD8 T cells and CTLA-4+ cells in CD8 T cells were irrelevant to the PD-L1 TPS in NSCLC patients.

Lung cancer is diagnosed at a late stage due to lack of early disease symptoms. Therefore an efficient treatment is necessary for prolonged disease free survival.In our study we recruited 124 patients NSCLC patients with adenocarcinoma and squamus cell carcinoma. All recuited patients had Programmed death-ligand 1 expression ≥50 (PD-L1)with DAKO technique. Immunotherapy was administered with as first line treatment. Re-biopsies were performed in the main lung lesion every 4 months with the restaging of the patient and also in the metastastic sites in other organs that occurred during treatment. PD-L1 expressed was evaluated in the biopsies of the metastatic sites.It appears thereafter that the PD-L1 expression could easily be claimed as a promising bio-index with a cutoff value 65, below which a negative prognosis of the disease progress will be evident and above that value a positive continuation of the disease will be prominent.The findings of this study suggest that the PD-L1-65 index works adequately either concerning the neo-metastatic sites or the patient disease responses. Re-biopsies in new metastastic sites are necessary since we probably have a new cancer and chemotherapy should be added. More studies should confirm are results and change the NSCLC treatment approach of these patients.

The objectives were to study the pattern of expression of PD-L1 in patients with carcinoma cervix and find out any relation with the various patient- and disease-related factors like histology, FIGO stage, lymph node metastasis and response to treatment. One hundred cervical cancer patients registered during 2018 who were suitable for radical treatment were identified. The paraffin-embedded, formalin-fixed cervical biopsy specimens of these patients were collected. Immunohistochemical staining for PD-L1 expression was performed on the cervical biopsy material. The test was considered positive if 50 per cent or more tumour cells or less than 50 per cent with intense staining were present. PD-L1 was positive in 25 of 99 (25.3%) cervical carcinoma samples. PD-L1 was positive in 18 of 81 (22%) squamous cell carcinomas, 7 of 16 (43.7%) adenocarcinomas and 0 out of 2 adenosquamous carcinomas. Twenty-nine per cent of patients with positive pelvic nodes expressed PD-L1 positivity. None of the patients with paraaortic node metastasis expressed PD-L1 positivity. No statistically significant associations were found between PD-LI positivity and menopausal status, haemoglobin level, histology, tumour size, FIGO stage, nodal involvement and response to treatment. One out of four patients had evidence of PD-L1 positivity in their cervical cancer. No association was found between PD-L1 expression and various clinicopathological factors and response to treatment. But follow-up studies are needed to observe any effect on disease-free or overall survival. Validation of scoring of PD-L1 expression and uniform reporting is required.

Advanced intrahepatic cholangiocarcinoma (iCCA) is not suitable for surgical treatment. Guided by the concept of precision medicine, preoperative systematic treatment may reshape the clinical outcomes of advanced intrahepatic cholangiocarcinoma patients. We describe the case of a 38-year-old female who has been diagnosed with stage IV intrahepatic cholangiocarcinoma with a high tumor mutational burden and positively programmed death-ligand 1 (PD-L1) expression. The patient was treated with programmed cell death 1 (PD-1) inhibitors combined with tyrosine kinase inhibitors (TKIs). After 7 cycles of combination therapy, she underwent radical resection and no tumor cells were found in the postoperative histopathological examination. In addition, the patient’s survival time had reached 25 months, as of August 2021. To date, this is the first case of successful radical resection after combined immunotherapy with TKIs for advanced PD-L1-positive intrahepatic cholangiocarcinoma with a high tumor mutational burden (TMB). The case provides a new approach to the treatment of advanced intrahepatic cholangiocarcinoma.

Pancreatic cancer is the seventh leading cause of death in developed countries and it still has a poor prognosis despite intense research in the last 20 years. Immunotherapy is a relatively new strategy in cancer treatment. The aim of immunotherapy is to block the immunosuppressive effect of tumoral cells. The PD1/PD-L1 axis has an important role in the inhibition of effector T cells and the development of regulatory T cells (Tregs). Blocking these checkpoints, and also inhibitory signals, leads to apoptosis of Tregs and increased immune response of effector T cells against tumoral antigens. Unfortunately, pancreatic cancer is generally considered to be a non-immunogenic tumor. Thus PD-1/PD-L1 inhibitors demonstrated poor results in pancreatic cancer, excepting some patients with MSI/dMMR (microsatellite instability/deficient mismatch repair). Furthermore, pancreatic cancer has a particular microenvironment with a strong desmoplastic reaction, increased interstitial fluid pressure, hypoxic conditions, and acidic extracellular pH, which promote tumorigenesis and progression of the tumor. Mismatch repair deficiency (dMMR) is correlated with a high level of mutation-associated neoantigens, most recognized by immune cells which could predict a favorable response to anti-PD-1/PD-L1 therapy. PD-1/PD-L1 molecules could be also found as soluble forms (sPD-1, sPD-L1). These molecules have a potential role in the prognosis and treatment of pancreatic cancer.

INTRODUCTION AND OBJECTIVE:We aim to evaluate the role of PD-L1 expression in the tumor microenvironment on oncological outcomes for patients treated with trimodality therapy (TMT) for muscle-invas...

OBJECTIVE To investigate the prognostic and predictive value of PD-L1 expression in operated non-small cell lung cancer (NSCLC) patients and to analyze its relationship with clinicopathological factors. MATERIAL AND METHOD A total of 90 patients with operable NSCLC were included in this retrospective single center study. Tumor blocks of patients were stained immunohistochemically with PD-L1 polyclonal antibody. When evaluated immunohistochemically and statistically, patients with tumor staining percentage of ≥5%, those with +2 and +3 membranous staining intensity, and those with ≥50% H-Score were considered positive. The relationship between PD-L1 expression status and clinicopathological features in addition to the prognostic effect of PD-L1 on survival were statistically analyzed. RESULTS The frequency of PD-L1 expression was 37%, 15% and 5% according to the staining percentage, staining intensity, and the H-Score, respectively. There was no significant relationship between PD-L1 expression and age, gender, smoking, tumor stage and histological subtype (p > 0.05). However, PD-L1 expression was relatively higher in patients < 65 years of age, men, smokers, patients with advanced tumor stage, and squamous cell subtype. Based on the analysis of the H-Score, no significant difference was noted regarding disease-free survival time between PD-L1 positive and PD-L1 negative patients (median 20 [95% CI 1.2-38.7] months vs. median 27 [95% CI 17.5-36] months, p=0.208). However, overall survival time was significantly shorter in PD-L1 positive compared to PD-L1 negative patients (median 24 months [95% CI 9.9-38] vs. median 48 months [95% CI 33.6-62.3], p=0.049). CONCLUSION In patients with high PD-L1 expression, the biological behavior of the cancer was more aggressive, and the life expectancy was shorter. PD-L1 expression seems to be a poor prognostic marker in NSCLC patients.

Although information on the PD-L1 expression and EGFR mutations in non-small cell lung cancer (NSCLC) is important for therapeutic strategies, the effect of these factors on postoperative recurrence and the association between each factor have remained unclear. We retrospectively assessed the PD-L1 expression and EGFR mutations in 280 NSCLC patients, and analyzed the associations by multivariate analyses. The hazard ratio (HR) of postoperative recurrence in cases with high (≥ 50%) PD-L1 expression regarding negative expression was 4.83 (95% confidence interval [CI] 1.51–15.5). The HR for the PD-L1 expression, considered a continuous variable, was 1.016 (95% CI 1.01–1.03). The HRs in cases with EGFR major and minor mutations were 0.42 (95% CI 0.14–1.25) and 0.63 (95% CI 0.18–2.15), respectively. The high PD-L1 (≥ 50%) expression was significantly associated with exon 21 L858R mutation (Ex21) of EGFR (odds ratio, 0.10; 95% CI 0.01–0.87). The risk of postoperative recurrence increased 1.016-fold for every 1% increase in the PD-L1 expression, and a marked increase in risk was observed for expression levels of ≥ 50%. Whereas EGFR mutations were not an independent risk factor. The high PD-L1 (≥ 50%) expression was negatively associated with Ex21. These findings may help identify NSCLC patients with an increased risk of postoperative recurrence.

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 TPSConclusionsThe 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.

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

Pembrolizumab plus chemotherapy is currently used in the first-line treatment of advanced non-small-cell lung cancer withoutLay abstract Non-small-cell lung cancer (NSCLC) is the most frequent type of lung cancer. Most NSCLC patients are diagnosed with advanced disease and only 10–15% of them are alive after 5 years. In the absence of specific tumor mutations, the currently recommended treatment is a combination of chemotherapy and immunotherapy with the monoclonal antibody pembrolizumab. The goal of immunotherapy is to prevent cancer from evading the immune system by interacting with molecules expressed at the surface of tumor cells (PD-L1) or immune cells (PD-1). A study comparing chemotherapy plus pembrolizumab versus pembrolizumab alone has never been performed in patients with a high level of PD-L1 expression on tumor cells. Therefore we designed the PERSEE study to compare these treatments in advanced-stage NSCLC patients with PD-L1 expression on ≥50% of tumor cells.

Immune checkpoint blocking therapy targeting the PD-1/PD-L1 axis has shown promising availability for triple-negative breast cancer (TNBC). Nevertheless, in some cases, targeting efficiency is low and efficient gene interaction networks need to be sought, which inspired the exploration that MCT4 and PD-L1 co-expression network analysis and potential regulatory mechanism research. In the paper, bioinformatics, Western blot, qRT-PCR, flow cytometry, biochemical analysis, multiple immunohistochemistry, CRISPR/Cas9 and lentiviral transduction for MCT4 knockout (sgMCT4/231 KO) or overexpression (pEGFP-N1-MCT4/231) were adopted. Analysis of database basis showed MCT4 (SLC16A3) and PD-L1 (CD274) were functionally correlated and highly expressed in TNBC cells, further MCT4 and PD-L1 were co-expressed (more than 50% PD-L1+MCT4+ cells) in tissue section of TNBC patients. The expression of PD-L1 in TNBC cell lines MDA-MB-231, MDA-MB-468 and BT-549 was sensitive to lactate concentration, and lowering MCT4 expression could downregulate PD-L1 expression through affecting the lactate concentration. These data suggests that MCT4 is positively associated with PD-L1 and the co-targeted therapy for TNBC may be a promising clinical treatment strategy.

Background Urinary microbiota is associated with the recurrence of bladder cancer, but the underlying mechanism remains unclear. The notion that microbiota can upregulate PD-L1 expression in tumors to promote immune escape have been demonstrated. We hypothesized that the urinary microbiota may be involved in the recurrence and progression of non-muscle invasive bladder cancer (NMIBC) by upregulating the PD-L1 expression. For proving this hypothesis, we firstly performed this study to characterize the potential urinary microbial community possibly associated with PD-L1 expression in male patients with NMIBC. Results The subjects (aged 43–79 years) based on their PD-L1 immunohistochemical results were divided into PD-L1-positive group (P group) and PD-L1-negative group (N group) respectively. We observed that P group exhibited higher species richness and diversity (based on Observed species and Ace index, both P P Leptotrichia, Roseomonas, and Propionibacterium) and decrease of some bacterial genera (e.g.,Prevotella and Massilia) were observed in P group as compared with N group. These findings indicate that these genera may affect the expression of PD-L1 through some mechanisms to be studied. PICRUSt analysis showed that several pathways involved in the metabolism of chemical compounds and immune-related disease were enriched in the PD-L1 negative group. Conclusion Our data indicate that urinary microbiota may be an important determinant of PD-L1 expression in male NMIBC patients. The findings of our study may facilitate subsequent study on the role and mechanism of urinary microbiota in the recurrence of NMIBC and may also pave a new way for the better application of PD1 or PD-L1 blockers in bladder cancer in the future.

This phase II study evaluated camrelizumab in different PD-L1 expression cohorts of patients with previously treated advanced/metastatic non-small cell lung cancer (NSCLC; NCT03085069, registered March 21, 2017). Patients who progressed during/after chemotherapy were enrolled and divided into four cohorts based on PD-L1 tumor proportion score (TPS). Patients with EGFR/ALK alterations and PD-L1 TPS ≥ 50% were also eligible. All enrolled patients received camrelizumab at 200 mg IV Q2W. The primary endpoint was objective response rate. A total of 146 patients were enrolled. As of data cutoff on Aug 20, 2020, the median follow-up was 29.5 months (95% CI 27.4–30.8). Objective response rate was 17.8% (95% CI 12.0–25.0) and improved with the increasing PD-L1 TPS (TPS

Background. A better understanding of tumor immunology can facilitate the development of new treatment strategies for various malignancies. Histologically assessed tumor-infiltrating lymphocytes (hTILs) and programmed cell death 1 ligand 1 (hPD-L1) have been established as prognostic or predictive biomarkers in certain subsets of breast cancer. However, the complexity of multiple types of immune cells is not fully understood. In this study, the immune cell fractions in breast cancer tissue and blood were evaluated to analyze their association with hTILs and hPD-L1. Methods. In total, 45 tumor and 18 blood samples were collected from breast cancer patients. The total leukocyte counts, proportions of 11 types of immune cells in the samples, and PD-L1 expression in each fraction were evaluated using multicolor flow cytometry for both the tumor and blood samples. The hTILs and hPD-L1 were evaluated with hematoxylin and eosin staining and immunohistochemistry respectively. Results. The immune cell composition of the blood showed a partial correlation with that of the tumor tissue; however, no significant association was found between the blood immune cell compositions and hTIL or hPD-L1 expression. A higher hTIL was associated with increased leukocyte infiltration as well as a higher proportion of CD4+ and CD8+ T cells and lower proportion of natural killer cells and natural killer T cells. PD-L1 was highly expressed in the monocyte/macrophage (Mo/Mφ), nonclassical monocyte (CD16+ Mo), myeloid-derived suppressor cell (MDSC), dendritic cell (DC), and myeloid dendritic cell (mDC) fractions in the tumor tissues. hPD-L1 positivity was associated with increased leukocyte infiltration in the tumor tissues and PD-L1 expression in Mo/Mφ, CD16+ Mo, MDSC, DC, and mDC fractions. Conclusion. There was a partial correlation in the composition of immune cells at the tumor site and that in the peripheral blood. A high proportion of hTILs reflects not only higher immune cell infiltration but also differences in the immune responses in the tumor microenvironment. Non-B-cell antigen-presenting cell fractions such as Mo/Mφ, CD16+ Mo, MDSC, DC, and mDC fractions are involved primarily in the PD-L1 pathway in the breast cancer microenvironments.

Cell-released nanovesicles can induce anti-leukemia immunity. Leukemia cell-derived exosomes (LEXs) are promising anti-tumor vaccine components for cancer immunotherapy. Nonetheless, LEX-based vaccines show modest potency in vivo, likely due to the presence of immunosuppressive PD-L1 proteins in the exosomes. We hypothesized that targeting exosomal PD-L1 could optimize LEX-based vaccines. To test this hypothesis, we compared the capacity of exosomes derived from PD-L1-silenced leukemia cells (LEXPD-L1si) and non-modified exosomes to induce anti-leukemia immunity.Lentivirus-mediated PD-L1 shRNA was used to downregulate PD-L1 expression in parental leukemia cells and LEXs. LEXPD-L1si were characterized by electron microscopy, western blotting, and flow cytometry, and their anti-leukemia immune effects were tested on immune cells and in animal models.In the present study, lentivirus-mediated PD-L1 shRNA successfully downregulated PD-L1 expression in parental leukemia cells and in LEXs. LEXPD-L1si induced better DC maturation and subsequently enhanced T-cell activation, as compared with non-modified LEXs. Consistently, immunization with LEXPD-L1si induced greater T-cell proliferation and Th1 cytokine release. LEXPD-L1si was a more potent inducer of antigen-specific cytotoxic lymphocyte (CTL) response. Finally, we vaccinated DBA/2 mice with exosome formulations to test their ability to induce both protective and therapeutic anti-tumor CTL responses in vivo. Vaccination with LEXPD-L1si strongly inhibited tumor growth and prolonged survival. Downregulation of exosomal PD-L1 expression in LEXs effectively induce more potent anti-leukemia immunity. Therefore our strategy for optimizing LEX-based vaccine has a potential application in leukemia immunotherapy.

PurposeT-cadherin is an immunoglobulin-like adhesion molecule which acts as a tumor suppressor gene, programmed cell death ligand 1 (PD-L1) is a cell surface protein that involves in the suppression of the immune system. This study aimed at exploring the correlation between T-cadherin and PD-L1, as well as their prognostic value in patients with HPV-negative head and neck squamous cell carcinoma (HNSCC). MethodsIn this study, immunohistochemical staining was used to determine the protein expression of T-cadherin and PD-L1 in 104 tissue specimens of HPV-negative HNSCC. Spearman linear correlation analysis was used to determine the association between protein expression of T-cadherin and PD-L1. Kaplan-Meier analysis was used to plot overall survival (OS) and disease-free survival (DFS) curves. Cox proportional hazards regression analysis was used to conduct univariate and multivariate analysis. ResultsThe results showed a large negative association between protein expression of T-cadherin and PD-L1 (r=-0.775, P

Aims: To explore the prognostic value of high PD-L1 expression on tumor cells (TC) and tumor-infiltrating immune cells (TIIC) in urothelial carcinoma (UC). Patients & methods: 162 UC specimens were evaluated for PD-L1 expression on TIIC and TC with the SP263 assay. High PD-L1 expression was defined as ≥25% staining. Results: High PD-L1 expression on TC in UC patients with stage T1–4 disease was associated with poor overall survival. However, high PD-L1 expression on TIIC in UC patients with stage T1–4 disease revealed favorable disease-free and overall survival; more significant differences were observed in patients with stages T2–4. Multivariate analysis revealed that high PD-L1 expression on TIIC was an independent prognostic predictor for better disease-free and overall survival. Conclusion: High PD-L1 expression on TIIC, but not on TC, is a favorable prognostic factor in UC.

FAPESP: Fundo de Amparo a Pesquisa do Estado de S~ao Paulo, Sao Paulo, BrazilFundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [2017/20928-9]

Introduction: The activity of immune checkpoint blockade including anti-cytotoxic T-lymphocyte associated protein-4 and anti-programmed cell death protein-1 monoclonal antibodies in hematologic malignancies is limited outside of classical Hodgkin lymphoma and primary mediastinal B-cell lymphoma. Tumor mutational burden (TMB), programmed death ligand-1 (PD-L1) expression, and microsatellite instability-high (MSI-H) are well-established biomarkers predicting response to checkpoint blockade in solid malignancies. In addition, tumors with high TMB, defined as ≥10 mutations/megabase (mut/Mb), and/or MSI-H are Food and Drug Administration (FDA) approved tissue agnostic biomarkers for treatment with pembrolizumab. The frequencies of high TMB, MSI-H, and expression pattern of PD-L1 across specific hematologic malignancies are undefined. Methods: Patients with hematologic malignancies who had next generation sequencing (NGS) performed by Foundation One Heme were identified. TMB and MSI were measured by NGS. TMB was classified as high if ≥10 mut/Mb and low if Results: A total of 390 patients with hematologic malignancies with NGS were identified. Forty eight of the 390 samples (12%) had a high TMB (Table 1). Twenty five of 45 (56%) patients with DLBCL had a high TMB (Table 2). The TMB was low in all myeloid malignancies tested. None of the 302 samples tested were MSI-H. PD-L1 IHC was performed on 86 samples. Eleven (13%) had high expression, 26 (30%) had low expression, and 49 (57%) had no expression of PD-L1 on the tumor cells (Table 1). The majority of samples with PD-L1 expression were mature lymphomas (81%). TMB and PD-L1 score had a significant linear relationship (R = 0.22,p= 0.04, 95% CI 0.01 - 0.41) (Figure 1). Conclusion: This study provides detailed characteristics of TMB, MSI status, and PD-L1 expression for hematologic malignancies. Notably, a subset of lymphomas had high TMB and/or PD-L1 expression. Biomarker driven studies of checkpoint blockade in hematologic malignancies with high TMB and/or PD-L1 expression are warranted. Disclosures Sokol: Foundation Medicine:Current Employment;Roche:Current equity holder in publicly-traded company.Kurzrock:Medimmune:Research Funding;Foundation Medicine:Research Funding;Konica Minolta:Research Funding;IDbyDNA:Current equity holder in private company;Pfizer:Consultancy, Research Funding;Sequenom:Research Funding;Bicara Therapeutics, Inc.:Consultancy;Incyte:Research Funding;Takeda:Research Funding;TopAlliance:Research Funding;Boehringer Ingelheim:Research Funding;CureMatch Inc:Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees;Grifols:Research Funding;Guardant:Research Funding;X Biotech:Consultancy;Neomed:Consultancy;Actuate Therapeutics:Consultancy;Roche:Consultancy;Merck Serono:Research Funding;Genentech:Research Funding;Debiopharm:Research Funding;CureMetrix:Membership on an entity's Board of Directors or advisory committees;OmniSeq:Research Funding;TD2/Volastra:Consultancy;Turning Point Therapeutics:Consultancy.Goodman:EUSA Pharma:Consultancy;Seattle Genetics:Consultancy.

Programmed death-ligand 1 (PD-L1) expression has been described in patients with malignant peritoneal mesothelioma (MPM), but treatment strategies utilising immune checkpoint inhibition are yet to be defined. Here, we examine levels of PD-L1 expression in MPM patients treated with systemic and/or intraperitoneal chemotherapy using tissue from patient tumour biopsies or resections at multiple time points. We found the mean PD-L1 expression was higher in those with a germline mutation and/or those with a higher somatic mutation burden. Moreover, PD-L1 expression was lower in patients who had received prior chemotherapy as compared to the treatment-naive cohort. Twenty patients who received chemotherapy, either systemic and/or peritoneal, between PD-L1 measurements showed marked heterogeneity. Six (30%) patients demonstrated upregulation of PD-L1, while eight (40%) demonstrated downregulation. Heterogeneity in PD-L1 expression in MPM before and after cytotoxic therapies may present an additional consideration when initiating immune checkpoint inhibition in this rare and challenging disease.

Purpose: Immunotherapy has been successfully utilized for treatment of gastric cancer, so the identification of clinicopathologic features that are predictive of response to this therapy is crucial. 18F-FDG PET/CT can provide information on the molecular phenotype of many malignant tumors. The correlation between 18F-FDG accumulation and PD-L1/PD-L1-TILs status in gastric cancer patients has not been investigated. The aim of the current study is to assess whether 18F-FDG accumulation is associated with PD-L1/PD-L1-TILs status, and whether 18F-FDG PET/CT may be useful for predicting PD-L1/PD-L1-TILs expression of gastric cancer. Results: Tumors with positive PD-L1 expression had higher SUVmax than in tumors with negative PD-L1 expression (15.0 ± 8.0 vs. 7.2 ± 4.2, respectively; P = 0.004). Tumors with positive PD-L1-TILs expression also had higher SUVmax than in tumors with negative PD-L1-TILs expression (10.3 ± 6.5 vs. 6.6 ± 3.7, respectively; P = 0.034). Multivariate analysis suggested that SUVmax remained significantly correlated with the status of PD-L1 (P = 0.043) and PD-L1-TILs (P = 0.016). PD-L1 expression was predicted with an accuracy of 67.2% when a SUVmax value of 8.55 was used as a cutoff point for analysis. Similarly, PD-L1-TILs expression was predicted with an accuracy of 64.2%, when a SUVmax value of 7.9 was used as the threshold for analysis. Conclusion: Higher 18F-FDG accumulation in gastric cancers is correlated with positive PD-L1/PD-L1-TILs expression. 18F-FDG PET/CT may be used to predict the status of PD-L1/PD-L1-TILs and thus aid in optimal treatment decision. Methods: A retrospective analysis was conducted on 64 patients with gastric cancer who underwent 18F-FDG PET/CT. SUVmax was calculated from the 18F-FDG accumulation of the primary tumor. The relationship between SUVmax and PD-L1/PD-L1-TILs status was analyzed.

Objective: To investigate the correlation and overlaps between PD-L1 expression and classical genomic aberrations in Chineselung adenocarcinoma (LADC) patients. Methods: We reviewed 428 consecutive, surgically resected cases of LADC from October 2015 to December 2016 from our center.PD-L1 expression was evaluated based on tumor proportion score (TPS). Correlation and co-occurrence of PD-L1 expression levelwith those of classical driver genes, such as EGFR, ALK, ROS-1, and KRAS and with clinical variables and disease-free survival(DFS) were analyzed. Results: Seventy of the 428 cases (16.4%) showed TPS ≥ 1%, and 21 cases (4.9%) showed TPS ≥ 50%. PD-L1 positive expressionwas significantly associated with male gender, smoking, advanced TNM stage, and solid histologic subtype. Both TPS ≥ 1% and ≥50% were correlated with the absence of an EGFR mutation (P < 0.001) and the presence of ALK rearrangement (P = 0.024).KRAS mutation was associated with TPS ≥ 50% (P = 0.035). PD-L1 positivity commonly overlapped with the alterations ofclassical driver oncogenes (58.5% with TPS ≥ 1% and 42.9% with TPS ≥ 50%). Approximately three-quarters of PD-L1 positivecases co-occurred with classical therapeutic-gene aberrations in cases with stage III/IV cancer or cancer progression. LADC couldbe divided into four subgroups based on the expression profile of current routine biomarkers for potential therapeutic strategies. Conclusions: PD-L1 expression is not only closely correlated with classic gene alterations but also commonly overlaps with theaberrations of classical driver oncogenes in Chinese LADC patients. These findings provide a useful overview of clinical strategiesthat rely on the profile of routinely used molecular biomarkers. Cite this article as: Wu J, Sun W, Wang H, Huang X, Wang X, Jiang W, et al.The correlation and overlaps between PD-L1 expression and classicalgenomic aberrations in Chinese lung adenocarcinoma patients: a single centercase series. Cancer Biol Med. 2019; 16: 811-21. doi: 10.20892/j.issn.2095-3941.2019.0209

Background/aim Pulmonary pleomorphic carcinoma (PPC) is rare, and few studies have reported its features. We assessed the clinicopathological features, surgical outcomes, oncogenic status and programmed death-ligand 1 (PD-L1) expression of PPC. Patients and methods We retrospectively reviewed data from 22 consecutive patients who underwent resection of PPC between 2007 and 2017. Results The predominant tissue type of the epithelial component was adenocarcinoma in 15 patients (68%) and the others in 7 patients (32%), and the 3-year disease-free survival rate tended to be better in patients with an adenocarcinoma component compared to patients with another component (40.0% vs. 17.1%, p=0.059). PD-L1 expression was observed in all eight tumors whose PD-L1 status could be examined and high PD-L1 expression (≥50%) was frequent (5/8, 63%). Conclusion A predominant adenocarcinoma epithelial component in PPC might be associated with better survival outcomes and high PD-L1 expression might be frequent in PPC.

Different studies have evaluated the comparability of various immunohistochemical assays for PD-L1 expression evaluation, with contrasting results. Besides the important issues related to analytic performance and comparability of validated assays, not all platforms are available in all laboratories; moreover, standardized assays are very expensive, and funding for PD-L1 testing is hard to obtain, especially in the research setting. One of the most widely used and inexpensive PD-L1 clones is E1L3N (Cell Signaling Technology, Danvers, MA), which is labeled for research use only. In this work, we wanted to further study and validate in a larger cohort the analytical performance of E1L3N clone on Ventana platform (Ventana Medical Systems, Tucson, AZ) and its comparability with assays SP263 and 22C3 run onto their dedicated platforms. Serial sections of tissue microarrays built from 165 cases of resected lung cancer were stained for E1L3N onto Ventana platform following a previously reported protocol and for 22C3 and SP263 assays onto their respective platforms following manufacturer's instructions. Overall, we found very high concordance when comparing E1L3N with SP263 at both 1% and 50% cutoffs. Lower concordance was found between E1L3N and 22C3 at both cutoffs; however, 100% sensitivity was found for E1L3N compared with both SP263 and 22C3 at 50% cutoff. Given the 100% sensitivity at 50% cutoff demonstrated by E1L3N in comparison with both SP263 and 22C3 and therefore the lack of false-negative cases, we propose an algorithm for PD-L1 testing in NSCLC when considering pembrolizumab as first-line therapy.

Background Although there have been several studies on concordance of different assays testing programmed cell death ligand‐1 (PD‐L1) expression using surgical specimens, studies using real‐world biopsy specimens are scarce. However, many of the non‐small cell lung cancer (NSCLC) cases requiring immunotherapy and thus PD‐L1 testing are unresectable having to rely on small biopsy results. Therefore, we sought to assess the concordance of two diagnostic assays (22C3 and SP263) in evaluating PD‐L1 expression using specimens from CT‐guided transthoracic needle biopsy (TNB) specimens in a routine clinical setting. Methods A total of 202 NSCLC cases that underwent CT‐guided TNB from April 2017 to February 2018 were retrospectively reviewed. Biopsy specimens tested with both 22C3 and SP263 assays were included. Concordance of PD‐L1 expression levels determined by two assays was assessed using intraclass correlation coefficient, and the agreement of dichotomized values at various cutoffs (1%, 25%, and 50%) were assessed using Cohen's κ coefficient of agreement. Results A total of 80 patients (M:F = 47:33, mean age: 68.0 years) were included in the study. Concordance of PD‐L1 expression levels was high (intraclass coefficient: 0.892) between 22C3 and SP263 assays. Agreements at cutoff levels of 1%, 25%, and 50% were also good, with κ values of 0.878, 0.698, and 0.790, respectively. Positive percent agreement was 93.2%, 100.0%, and 95.2% for agreements at 1%, 25%, and 50%. Conclusion There is a high concordance of PD‐L1 expression evaluated with 22C3 and SP263 assays using CT‐guided TNB specimens.

Aim: To identify whether PD-L1 expression and EGFR status are associated with response to treatment benefit in advanced non-small-cell lung cancer (NSCLC) patients receiving PD-1/PD-L1 inhibitors. Methods: The relevant studies were retrieved and systematic evaluation was conducted. Databases were searched until November 2018. Results: A total of 12 randomized controlled trials (RCTs) with 6932 patients were included. Patients with the higher PD-L1 expression level tend to have a longer progression-free survival (PFS), overall survival (OS) and overall response rate (ORR). PFS and OS were significantly prolonged in all the subgroups of PD-L1 expression levels. For patients with PD-L1 expression levels of ≥1%, overall response rates were significantly prolonged, but there was no difference in patients with PD-L1 expression levels of

Objective Pleomorphic carcinoma (PC) is a rare pulmonary epithelial malignant tumor with a poor prognosis. The objective of the present study was to investigate the programmed death-ligand 1 (PD-L1) expression in PC and its correlation between the clinicopathological factors and prognosis. Methods Clinical and pathological data of 35 patients with surgically resected PC encountered from 2002 to 2016 at our institution were collected. The PD-L1 expression on tumor cells was evaluated via immunohistochemistry (clone 22C3). We examined the correlation between the PD-L1 expression and patients' clinicopathological factors and their prognosis. Results A high PD-L1 expression (≥50%) was seen in 21 (60%) patients, and parietal-pleural invasion was significantly correlated with a high PD-L1 expression (p=0.012). The 5-year overall survival and relapse-free survival were 68.2% and 43.2%, respectively. Tumor size ≥50 mm (p=0.021), lymph node metastasis (p=0.023), and a high PD-L1 expression (p=0.047) were correlated with a short relapse-free survival. Since lymph node metastasis was an independent risk factor of a poor overall survival (p=0.012), patients with a high PD-L1 expression also tended to have a worse overall survival than those with low levels (p=0.081). Conclusion A high PD-L1 expression is frequently seen in PC. The PD-L1 expression is associated with parietal-pleural invasion and might indicate a poor prognosis.

Objective: To examine the expression of programmed death ligand 1 (PD-L1) in type I and type II epithelial ovarian cancers (EOC) and its associations with outcomes. Methods: Records of 132 women with EOC were reviewed. Immunostaining of PD-L1 was performed with formalin-fixed, paraffin-embedded specimens. Expression of PD-L1 was classified into four categories (0; 1+; 2+; 3+) according to intensity of expression. Expression of PD-L1 ≥2+ was deemed to be high. Results: Of the 132 women, 75 (56.8%) and 57 (43.2%) women had type I and type II tumors, respectively. Approximately 70% of cases exhibited high PD-L1 expression. There was no significant difference in the rate of high PD-L1 expression between the two EOC types (65.3% versus 59.6%). In type I tumors, high PD-L1 expression was associated with more advanced stages (51.0% versus 34.6%), greater recurrence (46.9% versus 26.9%), and shorter median progression-free survival (27 months versus 62 months) than low expression. In type II tumors, there were no apparent differences between high and low expression of PD-L1 in terms of the percentage of advanced-stage tumors (82.6% versus 79.4%), recurrence (56.5% versus 58.8%), and median progression-free survival (21 months versus 24 months). Conclusion: high PD-L1 expression is associated with worse oncological outcomes in type I EOC. This finding emphasizes the merit of further studies to confirm this promising result and to determine the potential role of PD-L1 blockade therapy in type I EOC.

Intratumor heterogeneity may contribute to the ambiguous clinical results on PD-L1 status as a predictor for immunotherapy response in patients with HNSCC. This decreases the utility of PD-L1 expression from single tumour biopsies as a predictive biomarker. In this prospective study, intratumor heterogeneity of PD-L1 expression in HNSCC was investigated with both Tumour Proportion Score (TPS) and Combined Positive Score (CPS). Thirty-three whole surgical specimens from 28 patients with HNSCC were included. PD-L1 expression in six random core biopsies from each surgical specimen was used to assess the concordance between multiple biopsies and the negative predictive value of a single negative core biopsy. With 1% cut off, 36% of the specimens were concordant with TPS and 52% with CPS. With a 50% cut-off value the concordance was 70% with TPS and 55% with CPS. Defining a tumour as positive if just a single-one of the biopsies was positive, the negative predictive value (NPV) of a single negative core biopsy was 38.9 and 0% (1% cut off), and 79.9% and 62.8% (50% cut off) for TPS and CPS, respectively. In conclusion, PD-L1 positivity varies markedly within the tumour, both with TPS and CPS, challenging the utility of this biomarker.

Background: Variations in fibroblast growth factor receptor 1 (FGFR1), which occur frequently, are common driver mutations of lung squamous cell carcinoma. Immune checkpoint inhibitors targeting programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1) are powerful anticancer weapons. Activation of FGFR1 leads to tumorigenesis through multiple downstream molecules, including Yes-associated protein (YAP), but whether and how FGFR1 regulates tumor immune evasion remain largely unclear. Methods: H520 and HCC95 cells were treated with siRNA and plasmids to increase or decrease the expression of FGFR1, YAP and PD-L1, as assessed by molecular assays of protein and mRNA expression. The interaction between YAP and PD-L1 was verified by chromatin immunoprecipitation. After FGFR1 knockdown by shRNA, cancer cells were cocultured with Jurkat T cells, and then cell proliferation and activity were assessed. In C57BL/6 mice, the tumor immune microenvironment was analyzed by flow cytometry, immunofluorescence and immunohistochemistry after FGFR1 knockdown. The effect of the combination of FGFR1 knockdown and PD-1 blockade was explored both in vitro and in vivo. Results: In H520 and HCC95 cells, FGFR1 upregulated PD-L1 expression via YAP, and YAP initiated the transcription of PD-L1 after binding to its promoter region. Both in vitro and in vivo, FGFR1 knockdown decreased tumor growth and reduced immune escape and reactivation of T cells. The combination of FGFR1 knockdown and PD-1 blockade synergistically exerted antitumor effects. In human LSQCC, the expression of fibroblast growth factor 2 (FGF2), the activator of FGFR1, was positively correlated with that of PD-L1 at the mRNA level. Conclusions: The FGFR1/YAP/PD-L1 regulatory axis mediates tumor-associated immune suppression in lung squamous cell carcinoma, and FGFR1 knockdown reactivates T cells in the tumor microenvironment. Synergistic inhibition of both FGFR1 and PD-1/PD-L1 may be a possible treatment for lung cancer patients.