Positive Programmed Cell Death-ligand 1 Expression Research Articles

Measure of minimal residual burden on circulating tumor cells with over-expression of programmed death-ligand 1 as a dynamic biomarker in patients with colorectal cancer.

e14553 Background: In stage III colorectal cancer (CRC) patients, the extent of oxaliplatin-combination as an adjuvant therapy is still undetermined. Approx. 25-50% Stage II-III CRC patients are known to develop recurrence and metastasis even after comprehensive treatment, attributed to occult disease and Minimal Residual Disease (MRD). Circulating Tumor Cells (CTCs) are bio-mechanistic extravasation source for micro-metastatic disease. CRC patients, with lower adjuvant therapy from 3 to 6 months are known to exhibit increased CTCs and positivity rate due to the emergence of resistant clones. Assays to detect CTCs and expression of Programmed Cell Death-Ligand 1 (PD-L1) as a dynamic biomarker simultaneously has wide clinical implications. Especially, when the tissue biopsy is not inadequate to detect molecular targets for immune checkpoint inhibitor (ICT) therapy. Methods: Retrospectively, 182 CRC cancer patients were analyzed for the presence of CTC and distribution at baseline and follow-ups (up to 0-4 follow ups). The peripheral blood 1.5 ml was analyzed using the OncoDiscover platform approved by CDSCO, India consisting multifunctional magneto-nanosystem mediated by anti-epithelial cellular adhesion molecule (EpCAM) antibody. CTCs were analyzed in patients with early stages- pre and post treatment, progressive disease, Disease Free Status (DFS) and in metastasis. The isolated cells were immune-stained to detect CK-18 +ve, CD45 -ve, DAPI +ve and PD-L1 +ve expression. PD-L1 expression in CTCs was validated by analyzing the linear intensity gradients of the fluorescence signals. CTCs were termed as PD-L1 -ve based on a weak or no detectable fluorescence signal and termed +ve based on a high fluorescence signal using automated image acquisition Zeiss microscope. Results: In a cohort of 182 CRC patient samples, n = 128 (70.3 %) showed the presence of CTCs. The fluorescence intensity for PD-L1 expression as a robust functional assay on CTCs for molecular characterization was developed. The distribution of CTCs ranged from 1-9. The mean fluorescence intensity value and cut-off for the expression of PD-L1 in CTCs was accounted to be ~1.02. Interestingly, in n = 54 (42.2 %) patients, CTCs showed positive expression of PD-L1. CTC +ve patients with PD-L1 expression were associated at all stages and even in early stage, progressive disease, and metastasis. Patients without any CTCs n = 54 (29.7%) either had clinically stable disease or were in DFS with no radio-graphical image. Conclusions: The presence of PD-L1 over-expression on CTCs is a dynamic biomarker in blood, showing the progression of disease even in patients with DFS status. CTC enumeration and assessing the PD-L1 expression on CTCs could offer highly individualized treatment plans in CRC patients.

Exploratory biomarker analysis in the phase III L-MOCA study of olaparib maintenance therapy in patients with platinum-sensitive relapsed ovarian cancer.

The prospective phase III multi-centre L-MOCA trial (NCT03534453) has demonstrated the encouraging efficacy and manageable safety profile of olaparib maintenance therapy in the Asian (mainly Chinese) patients with platinum-sensitive relapsed ovarian cancer (PSROC). In this study, we report the preplanned exploratory biomarker analysis of the L-MOCA trial, which investigated the effects of homologous recombination deficiency (HRD) and programmed cell death ligand 1 (PD-L1) expression on olaparib efficacy. HRD status was determined using the ACTHRD assay, an enrichment-based targeted next-generation sequencing assay. PD-L1 expression was assessed by SP263 immunohistochemistry assay. PD-L1 expression positivity was defined by the PD-L1 expression on ≥ 1% of immune cells. Kaplan-Meier method was utilised to analyse progression-free survival (PFS). This exploratory biomarker analysis included 225 patients and tested HRD status [N = 190; positive, N = 125 (65.8%)], PD-L1 expression [N = 196; positive, N = 56 (28.6%)], and BRCA1/2 mutation status (N = 219). The HRD-positive patients displayed greater median PFS than the HRD-negative patients [17.9 months (95% CI: 14.5-22.1) versus 9.2 months (95% CI: 7.5-13.8)]. PD-L1 was predominantly expressed on immune cells. Positive PD-L1 expression on immune cells was associated with shortened median PFS in the patients with germline BRCA1/2 mutations [14.5 months (95% CI: 7.4-18.2) versus 22.2 months (95% CI: 18.3-NA)]. Conversely, positive PD-L1 expression on immune cells wasassociated with prolonged median PFS in the patients with wild-type BRCA1/2 [20.9 months (95% CI: 13.9-NA) versus 8.3 months (95% CI: 6.7-13.8)]. HRD remained an effective biomarker for enhanced olaparib efficacy in the Asian patients with PSROC. Positive PD-L1 expression was associated with decreased olaparib efficacy in the patients with germline BRCA1/2 mutations but associated with improved olaparib efficacy in the patients with wild-type BRCA1/2. NCT03534453. Registered at May 23, 2018.

Clinicopathological and prognostic value of TIL and PD L1 in triple negative breast carcinomas

Triple negative breast cancer (TNBC), a highly aggressive subtype of breast cancer, accounts for 15 % of all diagnosed breast cancers. This group, which has the worst clinical outcome, high recurrence rate and poor prognosis, does not benefit from specific treatment. Therefore, there is a need to develop more effective biomarker and therapeutic strategies especially for this group. A positive level of immunity has been found to be associated with patient survival in various organ cancers. More specifically, tumor infiltrating lymphocytes (TIL) have been documented to have strong prognostic value. The programmed cell death 1 (PD 1) protein on the surface of T lymphocytes is activated by the Programmed cell death ligand 1 (PD-L1) protein on the cancer cell surface. PD- L1 is thought to form a pathway that results in suppression of antitumor responses when activated. Patients with breast cancer (BC) who underwent resection without neoadjuvant chemotherapy between 2010 and 2020 were included in this study. Of the 302 BCs examined, 21 constitute the group with TNBC. In our study, the mean age of the Triple positive breast cancer (TPBC) and TNBC groups was similar (55.67 ± 12.61 vs. 53.23 ± 8.21, p = 0.384). There was no significant correlation between TPBC and TNBC and tumor size, lymph node, histological grade, and PD-L1 positivity in the center of the tumor (all p-value >.05). It was observed that tumor stage was higher in patients with TNBC than in patients with TPBC (19 % vs. 1.1 %, p = .002). The Ki 67 proliferation index was found to be higher in patients with TNBC than in patients with TPBC (90.5 % vs. 41.8 %, p .001). Although not statistically significant, clinically, CD 3 and CD 8 immune scores with high tumor margin were higher in patients with TNBC than in patients with TPBC (90.4 % vs, 9.6 % and 85.7 % vs. 14.3 %, respectively). Positive expression of PD-L1 at the tumor margin was significantly higher in patients with TNBC than patients with TPBC (20.3 % vs, 52.4 %, p = .002). By Kaplan-Meier analysis, the survival distribution of CD 3 and CD 8 immunoscore, tumor central and margin PD-L1 values were compared. Mean follow-up was 136.18 months (range, 1 – 144 months); and the 10-year Overall Survival (OS) estimate for the population was 90.9 % (95 % CI, 85.5 – 96.7). In this study, this difference was not statistically significant according to the log-rank test. In this study, we aimed to evaluate the relationship between CD 3, CD 8 T lymphocyte immune score and PD-L1 expression at the tumor center and margin in TNBC, the prognostic value and clinicopathological significance of this relationship.

Evaluation of programmed cell death ligand 1 expression in a contemporary cohort of penile squamous cell carcinoma and its correlation with clinicopathologic and survival parameters: A study of 134 patients.

Penile squamous cell carcinomas (PCs) are rare malignancies with a dismal prognosis in a metastatic setting; therefore, novel immunotherapeutic modalities are an unmet need. One such modality is the immune checkpoint molecule programmed cell death ligand 1 (PD-L1). We sought to analyze PD-L1 expression and its correlation with various clinicopathologic parameters in a contemporary cohort of 134 patients with PC. A cohort of 134 patients with PC was studied for PD-L1 immunohistochemistry. The PD-L1 expression was evaluated using a combined proportion score with a cutoff of 1 or higher to define positivity. The results were correlated with various clinicopathologic parameters. Overall, 77 (57%) patients had positive PD-L1 expression. Significantly high PD-L1 expression was observed in high-grade tumors (P = .006). We found that 37% of human papillomavirus (HPV)-associated subtypes and 73% of other histotype tumors expressed PD-L1, while 63% of HPV-associated tumors and 27% of other histotype tumors did not (odds ratio, 1.35; P = .002 when compared for HPV-associated groups vs all others). Similarly, PD-L1-positive tumors had a 3.61-times higher chance of being node positive than PD-L1-negative tumors (P = .0009). In addition, PD-L1 high-positive tumors had a 5-times higher chance of being p16ink4a negative than PD-L1 low-positive tumors (P = .004). The PD-L1-positive tumors had a lower overall survival and cancer-specific survival than PD-L1-negative tumors. Overall, PD-L1 expression is associated with high-grade and metastatic tumors. Lower PD-L1 expression is observed more frequently in HPV-associated (warty or basaloid) subtypes than in other, predominantly HPV-independent types. As a result, PD-L1 positivity, including higher expression, portends lower overall and cancer-specific survival. These data provide a rational for further investigating PD-L1-based immunotherapeutics in PC.

Diagnostic value of programmed cell death-ligand 1 expression on circulating tumor cells in lung cancer: A systematic review and meta-analysis.

The expression of programmed cell death-ligand 1 (PD-L1) on circulating tumor cells offers a noninvasive method for the detection of PD-L1 expression in lung cancer, and could serve as a potential surrogate for cancer tissue. However, discrepant results make it difficult to apply PD-L1 on circulating tumor cells to clinical practice. Therefore, we conducted a meta-analysis to investigate the diagnostic value of PD-L1 on circulating tumor cells in lung cancer. To identify the relationship between the expression of PD-L1 on circulating tumor cells and lung cancer, the PubMed, Web of Science, Embase, China National Knowledge Infrastructure, and Wanfang databases were searched from inception to March 2023. The pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, diagnostic odds ratio, and the corresponding 95% confidence intervals were calculated to assess the diagnostic performance of PD-L1. We also conducted subgroup and sensitivity analyses. A total of 11 studies including 472 lung cancer patients were included in our study. The overall performance in terms of pooled sensitivity and specificity was 0.72 (0.52-0.86) and 0.54 (0.25-0.81), respectively. The positive likelihood ratio, negative likelihood ratio, and area under the curve were 1.57 (0.87-2.84), 0.52 (0.30-0.90), and 0.70 (0.66-0.74), respectively. Deeks' funnel plot test indicated no publication bias. Our analysis demonstrated that positive PD-L1 expression on circulating tumor cells (CTCs) exhibited a moderate diagnostic value in lung cancer, and CTCs may serve as a feasible alternative tissue analysis for the detection of PD-L1 in lung cancer.

Clinical and genetic characteristics in pancreatic cancer from Chinese patients revealed by whole exome sequencing.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal malignancies worldwide, mostly as a result of the absence of early detection and specific treatment solutions. Consequently, identifying mutational profiles and molecular biomarkers is essential for increasing the viability of precision therapy for pancreatic cancer. We collected blood and tumor tissue samples from 47 Chinese pancreatic cancer patients and used whole-exome sequencing (WES) to evaluate the genetic landscape. Our results showed the most frequently somatic alteration genes were KRAS (74.5%), TP53(51.1%), SMAD4 (17%), ARID1A (12.8%), CDKN2A (12.8%), TENM4 (10.6%), TTN (8.5%), RNF43(8.5%), FLG (8.5%) and GAS6 (6.4%) in Chinese PDAC patients. We also found that three deleterious germline mutations (ATM c.4852C>T/p. R1618*, WRN c.1105C>T/p. R369*, PALB2 c.2760dupA/p. Q921Tfs*7) and two novel fusions (BRCA1-RPRML, MIR943 (intergenic)-FGFR3). When compared to the Cancer Genome Atlas (TCGA) database, there is a greater mutation frequency of TENM4 (10.6% vs. 1.6%, p = 0.01), GAS6(6.4% vs. 0.5%, p = 0.035), MMP17(6.4% vs. 0.5%, p = 0.035), ITM2B (6.4% vs. 0.5%, p = 0.035) and USP7 (6.4% vs. 0.5%, p= 0.035) as well as a reduced mutation frequency of SMAD4 (17.0% vs. 31.5%, p = 0.075) and CDKN2A (12.8% vs. 47.3%, p < 0.001) were observed in the Chinese cohort. Among the 41 individuals examined for programmed cell death ligand 1(PD-L1) expression, 15 (36.6%) had positive PD-L1 expression. The median tumor mutational burden (TMB) was found to be 12muts (range, 0124). The TMB index was higher in patients with mutant-type KRAS MUT/TP53 MUT (p < 0.001), CDKN2A (p = 0.547), or SMAD4 (p = 0.064) compared to patients with wild-type KRAS/TP53, CDKN2A, or SMAD4. We exhibited real-world genetic traits and new alterations in Chinese individuals with cancer of the pancreas, which might have interesting implications for future individualized therapy and medication development.

Biomarkers predicting clinical outcomes in nasopharyngeal cancer patients receiving immune checkpoint inhibitors: A systematic review and meta-analysis.

Optimal biomarkers to select patients who will benefit most from immunotherapy remain lacking in nasopharyngeal cancer (NPC). This systematic review and meta-analysis aimed to evaluate the association between various biomarkers and clinical outcomes in NPC patients treated with immune checkpoint inhibitors (ICIs). Systematic searches of PubMed, Embase, Cochrane Library, and Web of Science databases were performed up to October 2022. Studies evaluating the association between biomarkers and intended outcomes of ICIs were included. The pooled odds ratio (OR) and hazard ratio (HR) with 95% confidence intervals (CIs) were calculated, respectively, for the objective response rate (ORR) and progression-free survival (PFS) under fixed or random-effect models. A total of 15 studies involving 1,407 patients were included. The pooled analysis indicated that NPC patients with lower plasma Epstein-Barr virus (EBV) DNA level at baseline (OR = 2.14, 95% CI: 1.46-3.14, P < 0.001), decreased EBV DNA load during immunotherapy (OR = 4.57, 95% CI: 2.24-9.34, P = 0.002) and higher programmed cell death-ligand 1 (PD-L1) expression (OR = 2.35, 95% CI: 1.36-4.09, P = 0.002) had superior ORR than the counterparts. No significant differences of ORR were observed between positive PD-L1 expression and negative PD-L1 expression (OR = 1.50, 95% CI: 0.92-2.45, P = 0.104), as well as higher tumor mutation burden (TMB) and lower TMB (OR = 1.62, 95% CI: 0.41-6.44, P = 0.494). Patients with lower plasma EBV DNA level at baseline obtained a significant benefit on PFS than those with higher plasma EBV DNA level (HR = 0.52, 95% CI: 0.42-0.63, P < 0.001). There were no differences in PFS between decreased EBV DNA load and increased EBV DNA load during immunotherapy (HR = 0.51, 95% CI: 0.22-1.17, P = 0.109), higher PD-L1 expression and lower PD-L1 expression (HR = 0.65, 95% CI: 0.42-1.01, P = 0.054), positive PD-L1 expression and negative PD-L1 expression (HR = 0.90, 95% CI: 0.64-1.26, P = 0.531), lower TMB and higher TMB (HR = 0.84, 95% CI: 0.51-1.38, P = 0.684). Lower baseline plasma EBV DNA level, decreased plasma EBV DNA during immunotherapy, and higher PD-L1 expression are reliable biomarkers predicting better response to ICIs treatment. Lower baseline plasma EBV DNA level was also associated with longer PFS. It is warranted to further explore and better illuminate the utility of these biomarkers in future clinical trials and real-world practice. https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022324434.

A Real-world Study on the Expression Characteristics of PD-L1 in Patients with Advanced EGFR Positive NSCLC and Its Relationship with the Therapeutic Efficacy of EGFR-TKIs

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) is the first choice for first-line treatment of advanced patients with EGFR positive non-small cell lung cancer (NSCLC). For advanced NSCLC patients with negative drive gene and positive programmed cell death ligand 1 (PD-L1) or highly expressed NSCLC patients, the first-line treatment recommends immune checkpoint inhibitors (ICIs) monotherapy or ICIs combined chemotherapy. Therefore, the first-line treatment strategy for advanced NSCLC patients with EGFR positive at different PD-L1 expression levels is worth further exploring. Many previous studies have suggested that the expression of PD-L1 is obviously affected by EGFR mutation, and the expression of PD-L1 is likely to be related to the mechanism of EGFR-TKIs resistance. The purpose of this study was to analyze the expression characteristics of PD-L1 in patients with advanced EGFR positive NSCLC and its relationship with the efficacy of EGFR-TKIs. 159 patients with newly diagnosed advanced NSCLC with EGFR positive (including 141 patients with EGFR sensitive mutations) were enrolled to analyze the relationship between clinicopathological characteristics and PD-L1 expression. The factors affecting the therapeutic effect of EGFR-TKIs in 141 patients with EGFR sensitive mutations were also explored. The PD-L1 expression of the included patients was classified according to the tumor promotion score (TPS): negative (TPS<1%) accounted for 47.2%, low expression (1%≤TPS<50%) accounted for 32.1%, and high expression (TPS≥50%) accounted for 20.7%. Among them, patients with solid predominant cancer cell pathomorphology classification are more likely to have high expression of PD-L1, accounting for 52.9% (P<0.0001). The median progression-free survival (mPFS) of patients with PD-L1 negative expression, low expression and high expression who received first generation EGFR-TKIs treatment were 12.4 months, 10.5 months and 3.7 months, respectively, with significant statistical difference (P<0.0001). During the EGFR-TKIs treatment, patients with a history of radiotherapy for lung lesions have a longer PFS benefit than those without a history of radiotherapy (mPFS: 17.0 months vs 9.3 months, P<0.0001). The expression level of PD-L1 in advanced EGFR positive NSCLC patients was significantly correlated with the pathomorphology classification of cancer cells. The efficacy of EGFR-TKIs in patients with PD-L1 overexpression NSCLC was significantly poor. PFS can be significantly prolonged during targeted therapy combined with radiotherapy of lung lesions.

Pathological features and immune microenvironment in HER-2 intratumoral heterogeneous breast cancers

Objective: To observe the clinical pathology features, and immune microenvironment of HER-2 intratumoral heterogeneity breast cancer. Methods: Thirty cases of HER-2 intratumoral heterogeneous breast cancer were retrospectively analyzed in Tianjin Medical University Cancer Institute and Hospital from November 2017 to June 2020. HER-2 expression was detected by immunohistochemistry and verified by dual color silver-enhanced in-situ hybridization (D-SISH). HER-2 intratumoral positive and negative regions were divided. The pathological characteristics, subtype, and the level of tumor infiltrating lymphocytes (TILs) and the expression of programmed cell death-ligand 1 (PD-L1) were evaluated respectively. Results: The proportion of HER-2 positive cells of the breast cancer ranged from 10% to 90%. The pathological type was mainly invasive non-special typecarcinoma. Six cases presented different pathological types between HER-2 positive and negative regions. The HER-2-positive areas included 2 cases of carcinoma with apocrine differentiation, and the negative areas included 2 cases of invasive micropapillary carcinoma, 1 case of invasive papillary carcinoma, and 1 case of carcinoma with apocrine differentiation. In HER-2 positive regions, 17 cases were Luminal B and 13 cases were HER-2 overexpressed types. There were 22 cases of Luminal B and 8 cases of triple negative tumors in the HER-2 negative areas. The levels of TILs in HER-2 positive and negative areas accounted for 53.3% (16/30) and 26.7% (8/30), respectively, with a statistically significant difference (P=0.035). The positive expression of PD-L1 in HER-2 positive area and HER-2 negative area were 6 cases and 9 cases, respectively. Among 8 cases with HER-2 negative regions containing triple negative components, 4 cases were positive for PD-L1 expression. Conclusions: In the case of HER-2 intratumoral heterogeneity, it is necessary to pay attention to both HER-2 positive and negative regions, and evaluate subtype separately as far as possible. For HER-2 intratumoral heterogeneous breast cancer containing triple negative components, the treatment mode can be optimized by refining the intratumoral expression of PD-L1.

Expression and correlation of PD-L1 and HER2 in oesophageal squamous cell carcinoma

AimsIn recent years, patients with programmed cell death-Ligand 1 (PD-L1)-positive oesophageal squamous cell carcinoma (OSCC) have been able to benefit from immunotherapy. However, method for improving the treatment efficacy of...

Combining PD-1 or PD-L1 inhibitors with chemotherapy is a good strategy for the treatment of extensive small cell lung cancer: A retrospective analysis of clinical studies.

To provide an updated systematic review and meta-analysis of published randomized controlled trials (RCTs) of the efficacy and safety of programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitors combined with chemotherapy versus chemotherapy alone in the treatment of extensive-stage small-cell lung cancer (ES-SCLC). PubMed, Web of Science, Embase, Clinicaltrials and the Cochrane Library were systematically searched to extract RCTs concerning the efficacy and safety of PD-1/PD-L1 inhibitors combined with chemotherapy versus chemotherapy alone in the treatment of ES-SCLC from the time of database inception to October 31, 2022. The literature was independently selected, information was extracted and the risk of bias of the RCTs was evaluated according to the inclusion and exclusion criteria. Stata14.0 was used for the meta-analysis. Six studies involving 2,600 patients were included in the analysis. The results of the meta-analysis showed that the combination of PD-1/PD-L1 inhibitors significantly improved the OS (HR: 0.73, 95% CI: 0.66-0.80; P<0.0001), prolonged PFS (HR: 0.66,95% CI: 0.55-0.79; P<0.0001) and did not increase overall incidence of treatment-related adverse events (TRAEs) (RR: 1.03, 95% CI: 0.97-1.09; P=0.330) in ES-SCLC patients compared with chemotherapy alone. The subgroup analysis found that patients with negative PD-L1 expression (< 1%) benefited in OS, whereas patients with positive PD-L1 expression (≥1%) had no statistically significant difference in OS. There was a statistically significant difference in PFS between PD-L1-negative (< 1%) and PD-L1-positive (≥1%) patients. The addition of a PD-1 inhibitor or PD-L1 inhibitor to the chemotherapy regimen can improve OS and prolong PFS in patients with ES-SCLC. PD-1/PD-L1 inhibitors combination chemotherapy significantly improves PFS and OS in ES-SCLC patients without increasing the overall incidence of TRAEs.

A Machine Learning Approach Using PET/CT-based Radiomics for Prediction of PD-L1 Expression in Non-small Cell Lung Cancer.

We explored the prediction of programmed cell death ligand 1 (PD-L1) expression level in non-small cell lung cancer using a machine learning approach with positron emission tomography/computed tomography (PET/CT)-based radiomics. A total of 312 patients (189 adenocarcinomas, 123 squamous cell carcinomas) who underwent F-18 fluorodeoxyglucose PET/CT were retrospectively analysed. Imaging biomarkers with 46 CT and 48 PET radiomic features were extracted from segmented tumours on PET and CT images using the LIFEx package. Radiomic features were ranked, and the top five best feature subsets were selected using the Gini index based on associations with PD-L1 expression in at least 50% of tumour cells. The areas under the receiver operating characteristic curves (AUCs) of binary classifications afforded by several machine learning algorithms (random forest, neural network, Naïve Bayes, logistic regression, adaptive boosting, stochastic gradient descent, support vector machine) were compared. The model performances were tested by 10-fold cross validation. We developed and validated a PET/CT-based radiomic model predicting PD-L1 expression levels in lung cancer. Long run high grey-level emphasis, homogeneity, mean Hounsfield unit, long run emphasis from CT, and maximum standardised uptake value from PET were the five best feature subsets for positive PD-L1 expression. The Naïve Bayes model (AUC=0.712), with a sensitivity of 75.3% and specificity of 58.2%, outperformed all other classifiers. It was followed by the neural network model (AUC=0.711), random forest (AUC=0.700), logistic regression (AUC=0.673) and adaptive boosting (AUC=0.604). PET/CT-based radiomic features may help clinicians identify tumours with positive PD-L1 expression in a non-invasive manner using machine learning algorithms.

P53 downregulates PD-L1 expression via miR-34a to inhibit the growth of triple-negative breast cancer cells: a potential clinical immunotherapeutic target.

Compared with other breast cancer subtypes, triple-negative breast cancer (TNBC) has poorer responses to therapy and lower overall survival rates. The use of an inhibitor of immune checkpoint programmed cell death ligand 1 (PD-L1) is a promising treatment strategy and is approved for malignant tumors, especially for TNBC. p53 regulates various biological processes, but the association between p53 and immune evasion remains unknown. miR-34a is a known tumor suppressor and p53-regulated miRNA that is downregulated in several cancers; however, it has not been reported in TNBC. Herein, we aimed to explore the regulatory signaling axis among p53, miR-34a and PD-L1 in TNBC cells in vivo and in tissue and to improve our understanding of immunotherapy for TNBC. p53-EGFP, p53-siRNA and miR-34a mimics were transfected into TNBC cell lines, and the interaction between miR-34a and PD-L1 was analyzed via dual-luciferase reporter assays. We found that p53 could inhibit the expression of PD-L1 via miR-34a and that miR-34a could inhibit both cell activity and migration and promoted apoptosis and cytotoxicity in TNBC. Furthermore, miR-34a agomir was injected into MDA-MB-231 tumors of nude mice. The results showed that miR-34a could inhibit tumor growth and downregulate the expression of PD-L1 in vivo. A total of 133 TNBC tissue samples were analyzed by immunochemistry; the proportion of positive expression of PD-L1 was 57.14% (76/133), and the proportion of samples with negative expression of PD-L1 was 42.86% (57/133). Our research may provide a novel potential target for TNBC.

Concordance of PD-L1 expression in triple-negative breast cancers in Chinese patients: A retrospective and pathologist-based study.

To compare the expression of programmed cell death ligand 1 (PD-L1) in different paraffin blocks from the same triple-negative breast cancers (TNBC) specimen and between matched primary tumors and lymph node metastases (LNMets). We also aim to determine the interobserver agreement between pathologists trained on PD-L1 (SP142) assay in assessing TNBC. 426 histologically confirmed TNBC cases, in which 85 have LNMets, were included in this study. A PD-L1 (SP142) assay was used to identify PD-L1 expression on tumor infiltrating immune cells (IC) and also on tumor cells (TC) in primary tumors and LNMets of TNBC by two trained pathologists. PD-L1 scoring and assessment were based on criteria in IMpassion 130 trial criteria. Concordance of PD-L1 expression in TNBC were analyzed using Kappa-test and assessed by the Kappa value. Prevalence of positive PD-L1 expression (PD-L1+) on tumor-infiltrating immune cells (PD-L1 IC+) (IC≥1%) in LNMets (49.4%) was higher than in the matched primary tumors (38.9%). Concordance of PD-L1 expression on IC between the two paraffin blocks from the same primary tumor specimen was substantial (P<0.000, Kappa = 0.627) and was identified in 83.1% (108/130) of the selected cases. For TNBC cases with matched primary and LNMets blocks, the concordance of PD-L1IC scoring between the two blocks was moderate (P<0.000, Kappa = 0.434). Interobserver agreement of PD-L1 assessment was 78.2% (P<0.000, Kappa = 0.567) in primary tumors and 61.4% (P<0.000, Kappa = 0.253) in the matched LNets. Substantial intratumor concordance of PD-L1 scoring of the primary tumors in TNBC patients was determined, implying that immunohistochemically detection using one representative block of the primary tumor should be enough to assign the expression status of PD-L1 in clinical practice. The prevalence of PD-L1+in lymph node metastases (LNMets) was higher than in the matched primary tumors, implying that PD-L1 detection in LNMets may provide additional PD-L1 expression information, especially in TNBC cases with PD-L1- in the matched primary breast tumors. Interobserver agreement of PD-L1 scoring in primary tumors was moderate while only fair in LNMets, implying that the additional training for PD-L1 assessment of TNBC LNMets specimens is recommended to enhance interobserver agreement. The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Features of patients with advanced EGFR-mutated non-small cell lung cancer benefiting from immune checkpoint inhibitors.

BackgroundAlthough immune checkpoint inhibitors (ICIs) generally show poor therapeutic efficacy in patients with epidermal growth factor receptor (EGFR) mutations, certain research indicate that a small proportion of these patients do respond to ICIs. The present study sought to identify the features of patients with EGFR mutations who might benefit from ICIs from multiple studies and discussed the optimal treatment paradigm for advanced non-small cell lung cancer (NSCLC) patients with EGFR mutations.MethodsThe profiles of 114 advanced NSCLC patients with EGFR mutations who received ICIs treatment were retrospectively reviewed. EGFR subtypes, programmed cell death ligand 1 (PD-L1) expression, and clinical characteristics regarding their impact on the efficacy of ICIs were investigated.ResultsPatients with major EGFR mutations (L858R or 19Del) had a shorter progression-free survival (PFS) and a lower objective response rate (ORR) as compared to patients with rare (20ins or G719X) and other EGFR mutations. Although not statistically significant, median overall survival (OS) tended to be longer in patients with negative (<1%) PD-L1 expression than with positive (≥1%) PD-L1 expression (15.61 vs. 7.40 months, p = 0.138). Median PFS and OS were significantly shorter in heavily treated patients (prior lines of therapy ≥3 lines vs. <3 lines: mPFS, 1.80 vs. 2.50 months, p = 0.003; mOS, 6.70 vs. 14.00 months, p = 0.031). ORR was also lower in patients who had received ≥3 prior lines of therapy compared to in those <3 prior lines of therapy (0.00% vs. 21.67%, p = 0.002).ConclusionPatients with major EGFR mutations showed poorer responses to ICIs than those with rare EGFR mutations. EGFR-mutated patients with lower PD-L1 expression showed a trend towards a longer OS after receiving ICIs. ICIs should be administered as early as possible to previously treated EGFR-mutated NSCLC patients. ICI-based combined therapies may be a direction for treatment of these patient subtypes in the future.

Prognostic role of PD-L1 expression in patients with salivary gland carcinoma: A systematic review and meta-analysis.

Although programmed cell death-ligand 1 (PD-L1) has been recognized as a potential marker in several cancers, the relationship between PD-L1 expression and survival in patients with salivary gland carcinoma (SGC) has remained unclear. We aimed to evaluate the association of PD-L1 expression with clinicopathological features and prognosis in SGC patients. The databases Ovid Medline, PubMed, Scopus, and EMBASE were searched for relevant studies that detected PD-L1 expression in SGC. The meta-analysis was performed according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA), and the reporting recommendations for tumor marker prognostic studies (REMARK) was used to assess the quality of research eligible for this meta-analysis. Included studies were assessed using the Quality in Prognosis Studies (QUIPS) tool. Odds ratios (ORs) with 95% confidence interval (CI) were calculated to estimate the correlation between PD-L1 expression and clinicopathological features. Hazard ratios (HRs) with 95% CI were applied to assess the association between PD-L1 expression and survival outcomes of patients. A total of ten studies (including 952 patients with SGC) were evaluated. The meta-analysis showed that positive PD-L1 expression in SGC was significantly associated with male patients, older age, Tumor stage, lymph node metastasis, high pathological grade, and non-adenoid cystic carcinoma subtype. The pooled data demonstrated that high PD-L1 expression was associated with poor overall survival and disease-free survival. There was no significant correlation between PD-L1 expression and progression-free survival or disease-specific survival of SGC patients. According to the meta-analysis, positive PD-L1 expression may play an important role as an effective marker of poor prognosis in patients with SGC. However, large-scale, prospective investigations are still needed to confirm the findings. The assessment of PD-L1 expression may aid in the personalized management of SGC.

Lower neutrophil-to-lymphocyte ratio and positive programmed cell death ligand-1 expression are favorable prognostic markers in patients treated with pembrolizumab for urothelial carcinoma.

Immune checkpoint inhibitors (ICIs) are effective in some cancer patients; however, they may show no efficacy in others. Predictive biomarkers are crucial for appropriately selecting the patients who receive ICI therapy. This study aimed to clarify the predictors of disease progression in urothelial carcinoma (UC) patients treated with an ICI, pembrolizumab. We analyzed the response patterns of 50 UC patients who were treated with pembrolizumab, as well as the association between survival and clinicopathological factors. Clinical factors included age, sex, body mass index, clinical courses, laboratory data, metastases, and adverse events. Pathological factors included special variant, squamous differentiation, programmed cell death ligand-1 (PD-L1) expression, CD8-positive lymphocytes density, and CDKN2A/p16 homozygous deletion. During pembrolizumab treatment, four (8%), 11 (22%), and eight (16%) patients achieved the best-case scenarios of complete response, partial response, and stable disease, respectively. Twenty-seven patients (54%) showed progressive disease. In this study, younger age, lower preoperative neutrophil-to-lymphocyte ratio (NLR), and positive PD-L1 expression were significantly correlated with longer progression-free survival and overall survival. Moreover, lower NLR and positive PD-L1 expression were independently associated with longer OS in multivariate analysis. Based on our observations, lower NLR and positive PD-L1 expression may be independent favorable prognostic markers in UC patients treated with pembrolizumab. These results suggest that both host and tumor status can reflect the effectiveness of pembrolizumab among patients with UC.

GemOX plus immune checkpoint inhibitor in combination with lenvatinib or NGS-guided targeted therapy in patients with biliary tract cancers.

e16133 Background: The combination of gemcitabine-based chemotherapy and immune checkpoint inhibitors has made great progress recently in advanced biliary tract cancer (BTC). Multi-target TKI lenvatinib or next-generation sequencing (NGS)-guided molecular targeted therapy are also promising. The aim of this study was to explore the anti-tumor effects of combined GemOX plus anti-PD-1 sintilimab and TKI either by lenvatinib or by NGS-guided targeted therapy if there is available target for local advanced or metastatic BTCs. Methods: This is a prospective single arm clinical study. Patients with local advanced or metastatic BTC were given intravenous infusion of standard GemOX (85mg/m2 oxaliplatin on day 1 and gemcitabine 1000mg/m2 on a 1-8-day schedule of a 3-week treatment cycle) plus 200mg q3w of sintilimab and lenvatinib or targeted therapy based on NGS (olaparib for BRCA1/2 mutation, dasatinib for IDH1/2 mutation, afatinib for EGFR mutation, lenvatinib for PDGFR and KIT mutation, lenvatinib for FGFR/KIT mutation). The primary end point was objective response rate (ORR), and the secondary end points were progression-free survival (PFS) and overall survival (OS). Tumor response was evaluated according to RECIST v1.1 criteria. Results: From November 2020 to December 2021, 22 patients with locally advanced or metastatic BTCs (6 GBC, 14 iCCA, 1 pCCA and 1 dCCA) were enrolled in the regimen, with an average age of 58.4 years. Partial response (PR) was achieved in 10 cases, stable disease (SD) in 9 cases and progression disease (PD) in 3 cases (13.6 %). The objective response rate (ORR) was 45.5%, and the disease control rate (DCR) was 86.4%. By December 31st, 2021, the median follow-up time was 13.1 months. The most common adverse events were anorexia (68.2%), nausea (68.2%), vomiting (36.36%), hair loss (45.5%) and bone marrow suppression (63.6%). During the treatment, the incidence of adverse reactions was 81.8%, and the incidence of grade 3/4 adverse events was 9.09%. For 14 patients with NGS, 5 patients were treated by targeting IDH2, EGFR, FGFR2, PDGFRA/KIT, BRCA2 and resulted in 1 SD and 4 PR with an ORR of 80% and DCR of 100%. The ORR and DCR were both 100% for 4 patients with programmed cell death ligand-1 (PD-L1) expression. While for the 3 patients with supper-progression markers such as RET, MDM2 and FGF14/STK24, there were 2 SD and 1 PD with an ORR of 0% and DCR of only 33%. Conclusions: In patients with advanced BTCs, the combination of GemOX plus sintilimab and lenvatinib or NGS-guided targeted therapy showed promising ORR and DCR, especially for the patients with positive PD-L1 expression and targetable gene alterations.

The clinicopathological significance of PD-L1 expression assessed by the combined positive score (CPS) in head and neck squamous cell carcinoma

The expression of programmed cell death-ligand 1 (PD-L1) is being used as a predictive biomarker for immunotherapy in head and neck squamous cell carcinoma (HNSCC). Our study was a retrospective cohort that assessed PD-L1 expression levels through immunohistochemistry (IHC) in 119 surgical specimens from HNSCC patients. The expression of PD-L1 was evaluated by IHC staining using the monoclonal antibody 22C3 (Dako) and the combined positive score (CPS). The relationship between the PD-L1 expression and clinicopathologic features was analyzed. 107 cases (89.9%) and 52 cases (43.7%) were positive for PD-L1 expression when the CPS cutoff value was set at 1 and 20 respectively. The tumor stage (P = 0.022) and tumor site (P = 0.004) were significantly correlated with the PD-L1 expression (CPS ≥ 1). Non-diabetic patients (P = 0.046) were corelated to positive PD-L1 expression (CPS ≥ 20). When evaluating PD-L1 expression in 40 laryngeal squamous cell carcinomas (LSC), the nodal stage was found to be significantly associated with high expression of PD-L1 (CPS ≥ 20) (P = 0.042). As for 36 patients with hypopharyngeal squamous cell carcinomas (HPSC), the positive PD-L1 expression (CPS ≥ 1) were typically younger (P = 0.030) and patients without type II diabetes (P = 0.040). We evaluated all possible clinical prognostic factors in the univariate Cox model, and there was no significant correlation between clinical characteristics and survival. The results of our findings may help to understand the association between the PD-L1 expression and clinicopathological characteristics, and it showed no significant correlation between the expression of PD-L1 and OS in HNSCC.

The worsening impact of programmed cell death ligand 1 in ovarian clear cell carcinomas.

To investigate the clinical significance of programmed cell death ligand 1 (PD-L1) expression in ovarian clear cell carcinoma (CCC). Patients with CCC who underwent primary surgery at our hospital between 1984 and 2014 were enrolled in this study. PD-L1 and mismatch repair (MMR) protein expression in tumor cells, tumor-infiltrating lymphocytes (TILs), including cluster of differentiation (CD) 8, CD4, forkhead box P3 (FOXP3), programmed cell death 1 (PD-1), and BAF250a, were evaluated using immunohistochemistry. The association between PD-L1 expression, clinicopathological features, prognosis, and expression of several proteins was investigated. Of the 125 patients with CCC, 17 had negative PD-L1 and 108 had positive PD-L1. Patients with positive PD-L1 expression showed a lower response to chemotherapy (p = 0.01). In addition, patients with positive PD-L1 showed worse progression-free survival (PFS, p = 0.01) and overall survival (OS, p = 0.01) than that in patients with negative PD-L1 expression. Multivariate analyses for PFS and OS showed that PD-L1 expression was an independent prognostic factor for PFS (hazard ratio [HR] 7.81, p < 0.01) and OS (HR 12.90, p < 0.01). PD-L1 expression was not associated with the expression of several TILs or proteins. The expression of PD-L1 was related to a lower response to chemotherapy and worse prognosis in CCC. These results may be useful for the development of new treatments.