Fas Ligand (FasL) in Association with Tumor-Infiltrating Lymphocytes (TILs) in Early Stage Cervical Cancer

Objective: To date, little is known about the roles of FasL and TILs in cervical cancer. This study aims to determine the correlation between FasL expression and TILs presence in cervical cancer. Methods: In this study, we analysed the FasL and TIL presence in 32 squamous cell carcinoma or adenocarcinoma that were obtained from early stage (≤ IIA2) cervical cancer patients using immunohistochemistry. The level of FasL and TIL was assessed qualitatively, and then quantified with the H-Score system. Results: Most of the patients were between 30 to 50 years old (59,4%), and had never taken pap smear examination before (96,9%). Based on the Pearson analysis of FasL and TIL presence, we found that FasL was inversely correlated with CD45 or TIL number when the level of FasL is above 140 and the CD45 is below 160. Based on Chi-Square test of FasL and TIL classification, there was a nine-fold odds ratio (OR) of lower TILs classification in high expression of FasL classification (OR 9, p=0.01). Conclusion: An inverse correlation between FasL expression and TILs level, that might indicate FasL-induced TILs apoptosis in tumor tissue, was observed. The strong inverse correlation between FasL and TILs presence showed some insight about the interactions between cancer cells and its surroundings inside of the cervical cancer tissue. This might also be further developed to tailor a prognostic marker that can predict the outcome of therapy in patients, not only in cervical cancer, but generally in all cancer.     

Programmed Death Ligand 1 (PD-L1) Expression in Epithelial Ovarian Cancer: A Comparison of Type I and Type II Tumors

Objective: To examine the expression of programmed death ligand 1 (PD-L1) in type I and type II epithelialovarian 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 wasclassified into four categories (0; 1+; 2+; 3+) according to intensity of expression. Expression of PD-L1 ≥2+ was deemedto 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 highPD-L1 expression between the two EOC types (65.3% versus 59.6%). In type I tumors, high PD-L1 expression wasassociated with more advanced stages (51.0% versus 34.6%), greater recurrence (46.9% versus 26.9%), and shortermedian progression-free survival (27 months versus 62 months) than low expression. In type II tumors, there were noapparent 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 versus24 months). Conclusion: high PD-L1 expression is associated with worse oncological outcomes in type I EOC. Thisfinding emphasizes the merit of further studies to confirm this promising result and to determine the potential role ofPD-L1 blockade therapy in type I EOC.     

原发性肝癌中PD-L1表达的调控机制

免疫疗法的应用是目前肿瘤研究的热点,尤其是免疫检查点抑制剂在晚期不可手术切除原发性肝癌的治疗中发挥了重要的作用。但不同患者免疫检查点抑制剂治疗疗效的差异较大,这引起了行业对PD-L1在肝脏肿瘤免疫逃逸中的调节机制的关注。PD-L1在肝癌中是由多个层次和多个信号通路调控的,包括表观遗传、转录调控、转录后调控和翻译后修饰。有研究发现PD-L1的高表达可能是影响原发性肝癌免疫治疗的主要因素,因此明确原发性肝癌中PD-L1的调控机制,可为原发性肝癌免疫治疗以及免疫联合治疗策略提供更多的依据。     

Neuroendocrine Differentiation,Microsatellite Instability,and Tumor-infiltrating Lymphocytes in Advanced Colorectal Cancer With BRAF Mutation

BackgroundApproximately 10% of metastatic colorectal cancer (mCRC) cases will harbor the BRAF p.V600E mutation (BRAF-mCRC) and have been associated with a poor prognosis. Although they are usually considered a unique clinical entity, biologic heterogeneity has been described. We performed an extensive clinicopathologic study of a multicenter series of BRAF-mCRC to highlight differences between tumors with microsatellite instability (MSI) and microsatellite stable tumors, focusing on both inflammatory profiles and neuroendocrine differentiation.MethodsWe included 59 BRAF-mCRC cases and collected the clinical data (ie, surgery, treatment, and follow-up). We evaluated MSI status, budding, lympho-angioinvasion, neuroinvasion, extent of active stroma, CD3⁺ and CD8⁺ intratumoral and peritumoral lymphocytes, programmed cell death ligand 1, p53, Ki-67, synaptophysin, and CDX2 expression.ResultsThe 22 MSI BRAF-mCRC cases were associated with the right side (P < .0001), an expansive grown pattern (P < .01), programmed cell death ligand 1 expression (P < .0001), high CD8 T-cell content (P = .0001), and lymph node metastases (P < .029). The 37 MSS BRAF-mCRC cases were characterized by a greater stromal component (P = .0002), pulmonary metastases (P = .095), and p53 and synaptophysin immunoreactivity (P = .004 and P = .001, respectively). Univariate analysis demonstrated that MSI and a high CD8 T-cell content were associated with a 34% (hazard ratio [HR], 0.66; 95% confidence interval [CI], 0.34-1.28; P = .2) and 33% (HR, 0.67; 95% CI, 0.45-0.99; P = .04) reduction in the risk of death, respectively. The combined presence of MSI and CD8 T-cell content decreased the hazard of mortality ≤ 63% (HR, 0.37; 95% CI, 0.14-0.97; P = .2), which was slightly reduced after multivariate analysis.ConclusionA simultaneous evaluation of MSI, CD8 T-cell content, and neuroendocrine markers could allow for the identification of subsets of BRAF-mCRC with a different prognosis and potential eligibility for specific treatments.     

Outcomes With First-line PD-1/PD-L1 Inhibition in Advanced Urothelial Cancer: A Single Institution Experience

BackgroundFirst-line PD-inhibition in cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer represents a novel clinical setting, with uncertainty concerning second-line outcomes. Specifying second-line treatment and outcomes will provide guidance in this new sequence. We performed a retrospective chart review to document the outcomes of these patients treated at our institution.Patients and MethodsOur cohort consisted of 43 patients with advanced urothelial cancer receiving first-line checkpoint inhibition. Baseline factors, programmed death-ligand 1 (PD-L1) status, treatments, and outcomes during and beyond the first line were obtained. Response was scored using Response Evaluation Criteria in Solid Tumors, version 1.1 criteria. Log rank tests were used to compare outcomes in prognostic subgroups, and outcome associations with PD-L1 status were analyzed with Fisher exact tests.ResultsA total of 43 patients received first-line atezolizumab or pembrolizumab from June 2014 until June 2018. The median age was 76.8 years, and the population was 74% male, with 60% having visceral metastases. Reasons for cisplatin ineligibility were Eastern Cooperative Oncology Group performance status 2%, 30%; renal insufficiency, 44%, and both, 21%. First-line objective response rate (ORR) was 30%, and complete response was 14%. The median overall survival was 11.7 months. Of 29 patients progressing, 17 received second-line treatment (most commonly, gemcitabine/carboplatin [10 patients]). The second-line response rate was 33%, and the ORR was 11%. The second-line median overall survival was 6.2 months. No association was found between PD-L1 status and outcomes.ConclusionOutcomes with first-line immunotherapy are consistent with historical outcomes. The ORR after first-line checkpoint inhibition falls short of historical comparators; however, the response rate compares favorably to those of chemotherapies used in previous second-line regimens. The older age and poorer performance status may have contributed to second-line outcomes.     

Prognostic Value of Testing PD-L1 Expression After Radical Cystectomy in High-risk Patients

Introduction

The use of cisplatin-based adjuvant chemotherapy (AC) after radical cystectomy (RC) is a highly controversial issue and has been infrequently used owing to the high rates of postoperative complications, cisplatin ineligibility, and lack of randomized trials. Checkpoint inhibitors such as nivolumab, pembrolizumab, or atezolizumab are currently being tested in phase III studies in the adjuvant setting owing to their more favorable safety profile compared with chemotherapy. The aim of the present study was to investigate whether compartmentalization of programmed cell death ligand 1 (PD-L1) expression in different locations of RC specimens influences recurrence-free survival (RFS) after RC.

Hot Spot and Whole-Tumor Enumeration of CD8+ Tumor-Infiltrating Lymphocytes Utilizing Digital Image Analysis Is Prognostic in Triple-Negative Breast Cancer

Background

CD8⁺ tumor-infiltrating lymphocytes (TILs) have emerged as a prognostic indicator in triple-negative breast cancer (TNBC). There is debate surrounding the prognostic value of hot spots for CD8⁺ TIL enumeration.

Programmed Cell Death Ligand (PD-L1) Expression in Stage II and III Lung Adenocarcinomas and Nodal Metastases

IntroductionProgrammed death ligand 1 (PD-L1) expression determined by immunohistochemistry (IHC) may serve as a predictive biomarker for anti–PD-1/PD-L1 therapies; however, little is known about intertumoral heterogeneity of PD-L1 expression determined by IHC in lung adenocarcinomas (ADCs), and there have been conflicting results on the prognostic role of PD-L1 expression in ADCs.MethodsPD-L1 expression was evaluated in resected stage II and III ADCs by using various cutoffs and correlated with clinicopathologic parameters and survival. PD-L1 expression was also compared between the primary tumor and lymph node metastases.ResultsThere were 109 study cases. PD-L1 expression was seen in 56 (51%), 43 (39%), and 19 (17%) when cutoffs of at least 1%, at least 5%, and at least 50%, respectively, were used. Abundant intratumoral CD8-positive T cells were a significant predictor of the expression in the primary tumor, with cutoffs of 1% and 5% (p < 0.001 for both) by multivariate analysis, whereas they were a nonsignificant predictor of the expression with a 50% cutoff (p = 0.076). PD-L1 expression was concordant between the primary tumor and nodal metastasis in most of the cases, but it was discrepant in up to 38%. The discrepancy was attributed in part to different predominant histologic patterns between the primary and metastatic tumors. In the entire cohort, PD-L1 expression with all cutoffs had no bearing on 5-year recurrence-free survival.ConclusionsPD-L1 expression is associated with abundant intratumoral CD8-positive T cells in resected ADCs, suggesting a predictive role of PD-L1 expression in anti–PD-1/PD-L1 therapies; however, the possible intertumoral heterogeneity of PD-L1 expression raises a concern about selecting the most appropriate sample for PD-L1 IHC.     

Programmed Death 1 and Programmed Death Ligand 1 Inhibitors in Advanced and Recurrent Urothelial Carcinoma: Meta-analysis of Single-Agent Studies

We performed a systematic review and meta-analysis on the response rates of patients with treatment-refractory urothelial carcinoma treated with programmed cell death 1 (PD-1) and programmed death ligand 1 (PD-L1) inhibitors. We reviewed the literature for prospective studies evaluating PD-1/PD-L1 inhibitors in refractory urothelial carcinoma patients, which formed the basis for US Food and Drug Administration approval of 5 different antagonistic antibodies targeting PD-1 or PD-L1 (atezolizumab, durvalumab, avelumab, nivolumab, and pembrolizumab). We considered studies examining PD-1/PD-L1–treated patients, which we identified using the following key terms in the Pubmed, Scopus, Web of Science, ClinicalTrial.gov, and Cochrane Library databases. Eligible studies had ≥ 20 patients each and reported response rates, duration of response, and overall survival (OS). We performed fixed and random-effects meta-analyses to model the point estimates for objective response rate and complete response. The median progression-free survival (PFS) and OS for studies reporting these statistics were evaluated. We found 10 eligible studies that met our inclusion criteria, providing extractable numerators and denominators for response rates, PFS, and OS for 1934 patients with metastatic urothelial carcinoma. The objective response rate was 18% (95% confidence interval, 15-22) for second-line or later therapies. The random-effects estimate for complete response was 4% (95% confidence interval, 3-5), including all disease locations and all PD-1 and PD-L1 inhibitors. Median OS and PFS were < 13 months and 3 months, respectively, across all studies, irrespective of PD-L1 expression. We found that the estimated response rates of agents included in this meta-analysis seem to be more favorable than other salvage therapies.     

JAK2 and PD-L1 Amplification Enhance the Dynamic Expression of PD-L1 in Triple-negative Breast Cancer

Background

Activation of the JAK/STAT pathway is common in triple-negative breast cancer (TNBC) and affects the expression of genes controlling immune signaling. A subset of TNBC cases will have somatic amplification of chromosome 9p24.1, encoding PD-L1, PD-L2, and JAK2, which has been associated with decreased survival.

Programmed Death Ligand 1 Immunohistochemistry in Triple-Negative Breast Cancer: Evaluation of Inter-Pathologist Concordance and Inter-Assay Variability

PurposeThe programmed death ligand 1 (PD-L1) SP142 assay with a 1% immune cell (IC) cutoff is approved for the selection of advanced triple-negative breast cancer (TNBC) patients for atezolizumab treatment. We aimed to evaluate the interobserver concordance of PD-L1 scoring and inter-assay variability of various PD-L1 assays in TNBC.MethodsThirty patients with primary TNBC were selected, and SP142, SP263, 22C3, and E1L3N assays were performed. PD-L1 staining in ICs and tumor cells (TCs) was scored by 10 pathologists who were blinded to the assay. The interobserver concordance among pathologists and the inter-assay variability of the four PD-L1 assays were analyzed. For SP142, the intraobserver concordance among the six pathologists was analyzed after training.ResultsThe adjusted means of PD-L1 IC scoring ranged from 6.2% to 12.9% for the four assays; the intraclass correlations showed moderate (0.584–0.649) reader concordance. The PD-L1 IC scoring with a 1% cutoff resulted in identical scoring in 40.0%–66.7% of cases and a poor to moderate agreement (Fleiss κ statistic [FKS] = 0.345–0.534) for the four assays. The SP142 assay had the widest range of positive rate (56.5%–100.0%), lowest number of cases with identical scoring, and lowest FKS at 1% cutoff. Pairwise comparison of adjusted means showed significantly decreased PD-L1 staining in SP142 compared with the other assays in both ICs and TCs. As for the intraobserver concordance in the SP142 assay, the overall percent agreement was 87.8% with a 1% IC cutoff. After training, the proportion of cases with identical scoring at a 1% IC cutoff increased to 70.0%; the FKS also increased to 0.610.ConclusionThe concordance of PD-L1 IC scoring among pathologists was low, at the 1% cutoff for the SP142 assay without training. SP142 showed the lowest PD-L1 expression in both IC and TC.     

BRAF Mutant Lung Cancer: Programmed Death Ligand 1 Expression,Tumor Mutational Burden,Microsatellite Instability Status,and Response to Immune Check-Point Inhibitors

Introduction

The efficacy of immune checkpoint inhibitors (ICPi) in BRAF mutant NSCLC is unknown.

Tumor-associated Macrophages and Neuroendocrine Differentiation Decrease the Efficacy of Bevacizumab Plus Chemotherapy in Patients With Advanced Colorectal Cancer

BackgroundIn the present study, we investigated the prognostic and predictive role of neuroendocrine differentiation (NED) and tumor-associated macrophage (TAM) infiltration in tumor tissue from patients with advanced colorectal cancer who had received bevacizumab plus chemotherapy.Patients and MethodsA total of 123 consecutive patients with advanced colorectal cancer who had received bevacizumab plus irinotecan/oxaliplatin-based combination chemotherapy were included in the present study. In addition to the clinicopathologic parameters, the presence of NED and the level of TAM infiltration were studied as covariates for survival analysis.ResultsThe median patient age was 57 years (range, 30-76 years). The chemotherapy backbone was FOLFIRI (folinic acid, 5-fluorouracil, irinotecan) for 75% of the patients. Univariate analysis showed that only NED and TAM infiltration were significant predictive factors for progression-free survival. Left-sided tumors and low TAM infiltration were favorable factors for overall survival on univariate analysis. However, the TAM level was the only independent prognostic factor for overall survival (hazard ratio, 0.301; 95% confidence interval, 0.102-0.892).ConclusionOur results suggest that increased TAM infiltration in tumor tissue and NED could decrease the efficacy of bevacizumab plus combination chemotherapy in patients with advanced colorectal cancer. TAM infiltration in the tumor tissue could be used as a biomarker in patients with advanced colorectal cancer receiving bevacizumab plus chemotherapy.     

PD-L1在结直肠癌原发灶中的表达及对肝转移微波消融术后复发的预测价值

目的探讨程序性死亡配体1(PD-L1)在结直肠癌(CRC)肝转移患者原发灶肿瘤细胞(TC)和肿瘤浸润免疫细胞(TIC)中的表达情况,及其对肝转移微波消融(MWA)术后复发的预测价值。方法回顾性收集28例CRC肝转移患者原发灶的石蜡包埋标本,采用免疫组织化学法检测其中PD-L1表达水平,分析其与临床特征的关系。Kaplan-Meier法和Log rank检验进行无复发生存(RFS)分析,Cox比例风险回归模型进行影响复发的多因素分析。结果PD-L1在CRC原发灶TC和TIC中的阳性率分别为14.3%(4/28)和46.4%(13/28)。CRC肝转移患者原发灶TIC的PD-L1表达与肝转移瘤最大径有显著关联(P<0.05),与肝转移MWA术后更差的RFS相关(P<0.05)。CRC肝转移患者原发灶TIC的PD-L1表达、肝转移瘤最大径>3 cm是影响肝转移MWA术后复发的危险因素(P<0.05)。结论CRC肝转移患者原发灶TIC的PD-L1表达可能会增加肝转移MWA术后复发的风险。     

Expression of PD-L1 in Early-Stage Invasive Breast Carcinoma and Its Relation to Tumor-Infiltrating Lymphocytes

Objectives: Immunotherapeutic targets became one of the promising approaches in breast cancer (BC), especially in advanced stage triple-negative subtype (TNBC). However, the role of programmed cell death ligand 1 (PD-L1) targeting in other BC subtypes, especially in early-stage carcinoma is less explored. We aimed in this study to investigate the prevalence of PD-L1 in early-stage invasive BC of different molecular subtypes and to elucidate its relation to tumor-infiltrating lymphocytes (TILS) density (cytotoxic and regulatory T-cells), established clinicopathological factors and patients’ outcome. Material and Methods: One hundred and nine cases of early-stage BC were enrolled in our study. Cases were classified into five molecular subtypes according to the Immunohistochemical data. PD-L1, FOXP3 and CD8 immunostaining were analyzed for all studied cases. PD-L1 expression was correlated with CD8+ cytotoxic T-cells, FOXP3+ regulatory T-cells, histopathologic parameters, BC molecular subtypes, 7-years disease-free survival (DFS) and overall survival (OS). Results: PD-L1 was expressed in 11% of the studied early-stage BC cases. It showed a significant correlation with high tumor grade (p= <0.001), development of metastasis (p=0.037), high FOXP3+ T-cell density (p= <0.001) and low CD8+ T-cells density (p= <0.001). PD-L1 expression was higher in TNBC (16.1%), followed by HER2/neu-enriched group (14.3%). All luminal A cases showed negative PD-L1 expression. PD-L1 was found to be an independent prognostic factor for patients’ survival (DFS; p=0.031 and OS: p=0.04). Conclusion: Although the impact of PD-L1 on early-stage BC outcomes had not been clearly established, our results indicated that PD-L1 is a negative prognostic marker in early settings. PD-L1 can serve as a new therapeutic target for patients with high-grade early-stage breast carcinoma.