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Background: Primary extragonadal choriocarcinoma (PEGCC) in male is rare. It is highly malignant, typically presents with distant metastasis at the time of diagnosis, and responds poorly to treatment. Because of its associated high levels of PD-L1, the PD-1/PD-L1 pathway is a likely therapeutic target. Herein, we report our experience of treating pediatric PEGCC in six boys at a tertiary hospital., Methods: We analyzed the data of six boys with pathologically confirmed PEGCC between 2009 and 2021. Their clinicodemographic and histopathological characteristics as well as treatments and clinical outcomes were retrieved from their medical charts., Results: The patients' median age was 15 (range: 12-17) years. The most common primary tumor site was the mediastinum (67%, 4/6), with one case each in the retroperitoneum (16.7%) and brain (16.7%). Except for the patient with brain PEGCC, all presented with metastasis at the time of diagnosis. The following metastatic sites were observed: the lungs (100%, 5/5), brain (3/5, 60%), liver (3/5, 60%), kidneys (2/5, 40%), and spleen (1/5, 20%). Most patients had dry cough, dyspnea, and hemoptysis at initial presentation, likely due to lung metastasis. Serum human chorionic gonadotropin (HCG) levels were highly elevated in all patients. All patients received platinum-based cytotoxic chemotherapy. The patient with brain choriocarcinoma underwent surgical tumor resection; all others underwent only surgical biopsy. Strong positive PD-L1 immunohistochemical staining was noted for two patients. One patient received the PD-L1 inhibitor pembrolizumab and achieved a good response. Our cohort's 1-year survival rate was 33.3%, with a median survival of 4.34 months. Serum HCG levels remained normal in the two survivors during follow-up visits., Conclusion: The poor response to current platinum-based chemotherapy remains a major challenge in the management of pediatric PEGCC. Adding pembrolizumab to a conventional chemotherapy regimen may improve the outcomes in boys with PEGCC., Competing Interests: Declaration of competing interest The authors have declared no conflicts of interest., (Copyright © 2024 Taiwan Pediatric Association. Published by Elsevier B.V. All rights reserved.)

The impact of gut and oral microbiota on the clinical outcomes of patients with oral squamous cell carcinoma (OSCC) is unknown. We compared the bacterial composition of dental plaque and feces between patients with OSCC and healthy controls (HCs). Fecal and dental plaque samples were collected from 7 HCs and 18 patients with OSCC before treatment initiation. Terminal restriction fragment-length polymorphism analysis of 16S rRNA genes was performed. Differences in bacterial diversity between the HC and OSCC groups were examined. We compared the occupancy of each bacterial species in samples taken from patients with OSCC and HCs and analyzed the correlation between PD-L1 expression in the tumor specimens and the occupancy of each bacterial species. The gut and oral microbiota of patients with OSCC were more varied than those of HCs. Porphyromonas and Prevotella were significantly more abundant in patients with OSCC than in HCs. The abundance of Clostridium subcluster XIVa in the gut microbiota of the PD-L1-positive group was significantly greater than that in the PD-L1-negative group. The oral and gut microbiomes of patients with OSCC were in a state of dysbiosis. Our results suggest the possibility of new cancer therapies targeting these disease-specific microbiomes using probiotics and synbiotics.

Background: The efficacy of immunotherapy for brain metastases from small cell lung cancer (SCLC) is relatively low, and the tumor microenvironment of SCLC brain metastases is still unknown. Therefore, we investigated the distribution of tumor-infiltrating lymphocytes (TILs) and the expression of programmed cell death-ligand 1 (PD-L1) in patients with brain metastases from SCLC to explore the tumor microenvironment of SCLC brain metastases., Methods: A retrospective analysis was performed on 12 surgical specimens of brain metastases from patients with SCLC treated in the Department of Neurosurgery of The First Affiliated Hospital of Anhui Medical University from June 2017 to June 2022. The inclusion criteria for this study were the following: (I) a pathologically confirmed diagnosis of SCLC brain metastases; (II) surgical resection of brain metastases; (III) age >18 years; (IV) and complete clinical data. Patient-related data were retrieved from the inpatient medical record system, telephone follow-up of patients date of death, and overall survival (OS). The immunofluorescence-based tissue microenvironment analysis panel (MAP) was utilized for the detection of TILs, including CD3, CD8, programmed cell death 1 (PD-1), and PD-L1, in formalin-fixed and paraffin-embedded archival specimens of brain metastases. The expression levels of PD-L1 in tumor cells were detected by immunohistochemistry. The correlation between the OS and the above-mentioned markers was analyzed in the 12 patients., Results: Twelve patients were included in the study. The patients' ages ranged from 51-78 years with a median of 68 years, with 1 female and 11 males. Among 12 patients with SCLC brain metastases: positive rates of CD3 + TILs in the tumor parenchyma vs. tumor stroma were 0.60%±0.94% vs. 1.76%±2.72% (P=0.01), respectively; positive rates of CD8 + TILs in the tumor parenchyma vs. tumor stroma were 0.80%±0.78% vs. 2.46%±3.72% (P=0.02), respectively. There was no co-expression of CD8 + and PD-1 + TILs in the tumor parenchyma of 11 cases, and the infiltration density of coexpressed CD3 + and PD-1 + TILs was more than 10/mm 2 in only 1 case. There was no coexpression of CD3 + and PD-1 + TIL in the stroma of 10 cases, and the infiltration density of CD8 + and PD-1 + TILs was more than 10/mm 2 in 2 cases. Immunohistochemistry was used to detect the expression of PD-L1 in 12 cases of SCLC metastatic lesions, and 3 cases (25%) were positive. Survival analysis showed that patients with positive intraepithelial CD3 + TILs had significantly longer OS [hazard ratio 3.383, 95% confidence interval (CI): 0.959-11.940; P=0.04]., Conclusions: Our study further demonstrated the immune microenvironment of SCLC brain metastases. The distribution of TILs in SCLC brain metastases is low and mainly distributed in the stroma, with the expression of PD-L1 in these tumor tissues being low. Further exploration of the immune microenvironment of SCLC brain metastases is of great significance for potential treatment., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-552/coif). M.T.M. receives royalties from Wolters Kluwer (UpToDate), outside this study. The other authors have no conflicts of interest to declare., (2024 Translational Cancer Research. All rights reserved.)

Background: The tumor microenvironment (TME) plays an important role in tumor progression and immunotherapy responses in non-small cell lung cancer (NSCLC). The programmed cell death 1 (PD-1)/ programmed cell death-ligand 1 (PD-L1) checkpoint is a central mediator of immunosuppression in the TME. However, there is still a need to identify additional biomarkers that could reflect the difference in TME and PD-L1 expression in NSCLC patients. To this end, we focused on the expression of G-protein-coupled receptor family C group 5 type A ( GPRC5A ) in NSCLC. GPRC5A , is a retinoic acid-inducible gene that plays multiple roles in NSCLC. However, little is known about the role of GPRC5A in regulating the TME and PD-L1. Our objective was to describe the critical role of GPRC5A expression in NSCLC in the setting of immune cell infiltration., Methods: We identified the relationship between GPRC5A expression and the clinicopathologic characteristics of NSCLC patients in the Fudan University Shanghai Cancer Center (FUSCC) cohort. Furthermore, we validated GPRC5A as a predictive biomarker by using public databases to reveal the relationship between GPRC5A expression and immune cell infiltration. To correlate the expression of GPRC5A with the spatial distribution of PD-L1 in NSCLC samples, we performed multiplex immunohistochemistry (mIHC)., Results: Low GPRC5A expression is associated with earlier pathological stage (pStage). Analysis of immune cell infiltration indicates there is a relationship between low GPRC5A expression and increased infiltration of CD8 + T cells, activated CD4 + T cells, and M1 macrophages within the TME. Furthermore, low GPRC5A expression is associated with an increased immunophenotype score (IPS) in NSCLC. Additionally, analysis of mIHC reveals there is a correlation between low GPRC5A expression and spatial distribution of tumoral PD-L1 expression., Conclusions: Our study revealed the relationship between low expression of GPRC5A and earlier pStage in NSCLC. Furthermore, we observed that low expression of GPRC5A is associated with increased infiltration of immune cells, higher IPS, and spatial distribution of PD-L1-positive tumor cells. Therefore, we speculate that low expression of GPRC5A is associated with immunotherapy, but further validation is still required., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-23-739/coif). The authors have no conflicts of interest to declare., (2024 Translational Lung Cancer Research. All rights reserved.)

Background: Primary cardiac angiosarcoma(PCA) has a low incidence rate and poor prognosis. Currently, no unified clinical treatment standards are available., Case Presentation: We report the case of a 48-year-old man presenting chest tightness, breathlessness, and dyspnea. Imaging and postoperative histopathologic studies confirmed PCA and that the tumor had invaded the entire right atrium. The patient developed progressive disease (PD) during postoperative radiotherapy. We used immunotherapy combined with targeted therapy based on the results of molecular profile and evaluation of tertiary lymphoid structures (TLSs) and programmed cell death-ligand 1 (PD-L1). After treatment, the metastatic lymph nodes of the patient were reduced to a certain extent, indicating that combination therapy was effective., Conclusion: To the best of our knowledge, this is the first report of radiotherapy combined with anti-PD-1 and tyrosine kinase inhibitors(TKI) for PCA. In addition, this is the first report on immunotherapy for PCA based on new evaluation methods, including TLSs, PD-L1, and genomic profile., (© 2024. The Author(s).)

Evidence recently showed that pleiotropic cytokine interferon-gamma (IFN-γ) in the tumor microenvironment (TME) plays a positive role in hepatocellular carcinoma (HCC) progression through the regulation of liver cancer stem cells (LCSCs) in HCC. The present study explored the role and potential mechanism of mitochondrial programmed cell death-ligand 1 (PD-L1) and its regulation of ferroptosis in modulating the cancer stemness of LCSCs. It was shown that mimicking TME IFN-γ exposure increased the LCSCs ratio and cancer stemness phenotypes in HCC cells. IFN-γ exposure inhibited sorafenib (Sora)-induced ferroptosis by enhancing glutathione peroxidase 4 (GPX4) expression as well reactive oxygen species (ROS) and lipid peroxidation (LPO) generation in LCSCs. Furthermore, IFN-γ exposure upregulated PD-L1 expression and its mitochondrial translocation, inducing dynamin-related protein 1 (Drp1)-dependent mitochondrial fission and correlating with glycolytic metabolism reprogramming in LCSCs. The genetic intervention of PD-L1 promoted ferroptosis-dependent anti-tumor effects of Sora, reduced glycolytic metabolism reprogramming, and inhibited cancer stemness of HCC in vitro and in vivo. Our results revealed a novel mechanism that IFN-γ exposure-induced mitochondrial translocation of PD-L1 enhanced glycolytic reprogramming to mediate the GPX4-dependent ferroptosis resistance and cancer stemness in LCSCs. This study provided new insights into the role of mitochondrial PD-L1-Drp1-GPX4 signal axis in regulating IFN-γ exposure-associated cancer stemness in LCSCs and verified that PD-L1-targeted intervention in combination with Sora might achieve promising synergistic anti-HCC effects., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Ramucirumab, an anti-vascular endothelial growth factor receptor (VEGFR) monoclonal antibody (mAb), inhibits angiogenesis and reduces tumor activity. Programmed cell death-ligand 1 (PD-L1) might act upon VEGFR2 to induce cancer cell angiogenesis and metastasis. Herein, we investigated the efficacy of combining ramucirumab and paclitaxel according to the status of PD-L1 expression in patients with advanced gastric cancer (AGC)., Methods: This analysis included AGC patients who received ramucirumab plus paclitaxel as 2 nd line therapy between December 1, 2018, and February 28, 2022, at Samsung Medical Center. All patient data analyses included an evaluation of PD-L1 expression using the combined positive score (CPS). We analyzed the efficacy and the survival of patients according to their PD-L1 expression., Results: We included 117 patients in this analysis, and 80 patients (68.4%) had a PD-L1 CPS of one or more, 37 (31.6%) had five or more, and 19 (16.2%) had ten or more scores. Progression-free survival (PFS) and overall survival (OS) did not differ significantly between patients with a PD-L1 CPS of less than one and one or more {PD-L1 <1% vs. PD-L1 ≥1%; PFS: median 3.6 months [95% confidence interval (CI): 2.4-4.8 months] vs. median 4.1 months (95% CI: 3.5-4.7 months), P=0.93; PD-L1 <1% vs. PD-L1 ≥1%; OS: median 7.0 months (95% CI: 5.4-8.6 months) vs. median 8.1 months (95% CI: 6.4-9.8 months), P=0.32}. PFS and OS did not differ significantly between patients with a PD-L1 CPS of less than 5 and 5 or more [PD-L1 <5% vs. PD-L1 ≥5%; PFS: 3.9 months (95% CI: 3.3-4.5 months) vs. 4.4 months (95% CI: 3.0-5.8 months), P=0.57; OS: 7.4 months (95% CI: 6.5-8.3 months) vs. 10.0 months (95% CI: 1.1-18.9 months), P=0.07]. Interestingly, with a PD-L1 CPS cutoff of 10, PFS and OS did differ significantly [PD-L1 <10% vs. PD-L1 ≥10%; PFS: 3.8 months (95% CI: 3.3-4.3 months) vs. 5.7 months (95% CI: 4.1-7.3 months), P=0.05; OS: 7.2 months (95% CI: 6.5-7.9 months) vs. 18.9 months (95% CI: 6.5-31.3 months), P=0.04]., Conclusions: No biomarkers have been established to predict survival times after ramucirumab plus paclitaxel treatment. This analysis suggests that a PD-L1 CPS cutoff of 10 might be novel a biomarker to predict the survival of AGC patients treated with ramucirumab and paclitaxel., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-23-418/coif). The authors have no conflicts of interest to declare., (2023 Journal of Gastrointestinal Oncology. All rights reserved.)

Background and Objective: Immune checkpoint inhibition has shed light on a new era in cancer therapy, and randomized clinical trials have demonstrated that a meaningful portion of the overall population of metastatic gastric cancer (GC) patients may derive clinical benefit from immunotherapy, which raises the relevance in identifying predictive biomarkers. Programmed cell death-ligand 1 (PD-L1) expression has demonstrated a significant association between level of expression and the magnitude of benefit derived from immune checkpoint inhibition in GC. Nevertheless, this biomarker shows several pitfalls that must be considered in the therapeutic decision to incorporate immune checkpoint inhibition as the standard of care of GC, such as spatial and temporal heterogeneity, interobserver variability, immunohistochemistry (IHC) assay, and influence by chemotherapy or radiation therapy., Methods: In the present comprehensive review, we revised the main studies regarding PD-L1 evaluation in GC., Key Content and Findings: Here we describe the molecular characteristics of the tumor microenvironment in GC, the obstacles in the interpretation of PD-L1 expression and present the data of the clinical trials that have evaluated the efficacy and safety of immune checkpoint inhibition and the association with the biomarker expression, both in first-line and later lines of therapy., Conclusions: From the emerging predictive biomarkers for immune checkpoint inhibition, PD-L1 has demonstrated a meaningful association between level of expression in tumor microenvironment and the magnitude of benefit derived from immune checkpoint inhibition in GC., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-22-1133/coif). RDP reports honoraria for lectures from Servier, BMS, MSD and Lilly. She also reports consulting fees from BMS and Lilly as well as support for attending meetings from Astrazeneca and Daiichi and Advisory Boards from AztraZeneca, Daiichi, BMS, Lilly and Servier. MCMM reports honoraria for lectures from Lilly and support for attending meetins from Pfizer. AJ reports consulting fees from Bayer, Lilly, Servier, BMS and Merck. He also reports honoraria for lectures from BMS and Astellas. MG reports honoraria for lectures from Servier, BMS, MSD, Amgen and Lilly. She also reports support for attending meetings from Pfizer, AstraZeneca and Daiichi. The author receives consulting fees from Servier and BMS and also has participated on advisory boards from AstraZeneca, Daiichi, BMS, Lilly, Servier. JF reports honoraria for lectures from Bayer and Servier, support for attending meetings from Bayer and Servier and participation in Advisory Boards for Servier. BS reports honoraria for lectures from Janssen and Servier. TP has received support for attending meetings and travel from IPSEN. ACA reports honoraria for lectures from MSD, AstraZeneca, IPSEN, Servier, Norvartis and Daiichi. PHD reports honoraria for lectures from AstraZeneca and Sanofi. AP reports honoraria for lectures from Servier, MSD, Zodiac, Amgen and AstraZeneca. FL reports that honoraria for lectures from Servier, BMS, MSD, Lilly, and AstraZeneca. She also reports support for attending meeting from AstraZeneca, BMS and Lilly and participation in advisory boards with Servier. MS reports honoraria for lectures from Servier and has received support for attending meetings and/or travel from IPSEN. The other authors have no conflicts of interest to declare., (2023 Journal of Gastrointestinal Oncology. All rights reserved.)

Introduction: Programmed cell death-ligand 1 (PD-L1) is a biomarker for prediction of the clinical efficacy of immune checkpoint inhibitors in various cancer types. The role of cytokines in regulation of PD-L1 expression in tumor cells has not been fully characterized, however. Here we show that interleukin-1β (IL-1β) plays a key role in regulation of PD-L1 expression in non-small cell lung cancer (NSCLC)., Methods: We performed comprehensive screening of cytokine gene expression in NSCLC tissue using available single-cell RNA-Sequence data. Then we examined the role of IL-1β in vitro to elucidate its induction of PD-L1 on NSCLC cells., Results: The IL-1β gene is highly expressed in the tumor microenvironment, particularly in macrophages. The combination of IL-1β and interferon-γ (IFN-γ) induced a synergistic increase in PD-L1 expression in NSCLC cell lines. IL-1β and IFN-γ also cooperatively activated mitogen-activated protein kinase (MAPK) signaling and promoted the binding of downstream transcription factors to the PD-L1 gene promoter. Furthermore, inhibitors of MAPK signaling blocked upregulation of PD-L1 by IL-1β and IFN-γ., Discussion: Our study reports high levels of IL-1β in the tumor microenvironment may cooperate with IFN-γ to induce maximal PD-L1 expression in tumor cells via activation of MAPK signaling, with the IL-1β-MAPK axis being a promising therapeutic target for attenuation of PD-L1-mediated suppression of antitumor immunity., Competing Interests: Author KT has received honoraria from Chugai Pharmaceutical, AstraZeneca, Ono Pharmaceutical, Bristol-Myers Squibb, Eli Lilly, Takeda Pharmaceutical, Daiichi-Sankyo, and MSD. Author EI has received honoraria from Chugai Pharmaceutical and AstraZeneca. Author IO has received honoraria and research funding from Chugai Pharmaceutical, AstraZeneca, Ono Pharmaceutical, Taiho Pharmaceutical, MSD, Eli Lilly, Boehringer Ingelheim, and Bristol-Myers Squibb as well as honoraria from Pfizer and research funding from Astellas, Novartis, Takeda Pharmaceutical, Daiichi Sankyo, Haihe Biopharma and AbbVie. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Hirayama, Tanaka, Tsutsumi, Nakanishi, Yamashita, Mizusaki, Ishii, Ota, Yoneshima, Iwama and Okamoto.)

More than 60 years ago, disulfiram (DSF) was employed for the management of alcohol addiction. This promising cancer therapeutic agent inhibits proliferation, migration, and invasion of malignant tumor cells. Furthermore, divalent copper ions can enhance the antitumor effects of DSF. Molecular structure, pharmacokinetics, signaling pathways, mechanisms of action and current clinical results of DSF are summarized here. Additionally, our attention is directed towards the immunomodulatory properties of DSF and we explore novel administration methods that may address the limitations associated with antitumor treatments based on DSF. Despite the promising potential of these various delivery methods for utilizing DSF as an effective anticancer agent, further investigation is essential in order to extensively evaluate the safety and efficacy of these delivery systems., (© 2023. The Author(s).)

Background and Objective: Triple negative breast cancer (TNBC) represents a highly aggressive breast cancer subtype, historically managed with chemotherapy regimens predominantly involving anthracyclines and taxanes, yielding unfavorable prognoses. This review endeavors to offer a thorough examination of the present state of treatment strategies for early stage triple negative breast cancer (eTNBC), with a particular emphasis on immunotherapy modalities, combination therapies, predictive biomarkers, and ongoing clinical trials. The principal aim of this review is to meticulously assess the available literature, ascertain significant discoveries, and engage in discussions regarding their potential implications for future research endeavors, clinical applications, and policy formulation., Methods: This review was conducted using PubMed and Google Scholar databases, with the latest update performed in March 2023. The search strategy was designed to ensure a comprehensive analysis of the literature, with a focus on recent advancements., Key Content and Findings: We critically assess the current eTNBC treatment landscape, covering efficacy and limitations of monotherapy, combination therapies, and predictive biomarkers. We highlight promising results from recent trials, address controversies surrounding chemotherapy, and explore optimal approaches for adjuvant and neoadjuvant therapy (NAT). Insights into personalized treatment strategies, ongoing trials, and future perspectives are provided, advancing our understanding of therapeutic options for eTNBC., Conclusions: Through a comprehensive analysis of the literature, this review highlights the potential of immunotherapy, particularly in combination with chemotherapy, as a promising approach for treating eTNBC. However, further research is warranted to optimize treatment strategies, refine patient selection criteria, and identify reliable biomarkers for predicting response to immune checkpoint inhibitors (ICIs). The findings of this review hold significant implications for future research, clinical practice, and policy-making, offering valuable insights into the current challenges and advancements in eTNBC treatment. Ultimately, this knowledge can contribute to improved patient outcomes, enhanced quality of life, and the development of more effective therapeutic approaches for eTNBC., Competing Interests: Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tbcr.amegroups.org/article/view/10.21037/tbcr-23-17/coif). QL serves as an unpaid editorial board member of Translational Breast Cancer Research from March 2022 to February 2024. The other author has no conflicts of interest to declare., (2023 Translational Breast Cancer Research. All rights reserved.)

Background: Lung adenocarcinoma, as a common histological type in lung cancer, the overall survival is very low, and the prognosis is poor because it is difficult to find and easily recurs. Therefore, this study aimed to explore the role of the secreted protein beta-1,3-N-acetylglucosaminyltransferase 3 (B3GNT3) in the development of lung adenocarcinoma and to evaluate its potential significance for early clinical biomarker screening., Methods: The mRNA expression profiles of patients with lung adenocarcinoma and normal controls were analyzed via The Cancer Genome Atlas (TCGA) database. Serum samples of clinical lung cancer patients and healthy people were obtained, and the differences in B3GNT3 expression in different stages of lung adenocarcinoma and in healthy tissues were compared. Kaplan-Meier (K-M) curves were drawn to clarify the influence of high and low expression of B3GNT3 on the prognosis of patients. Peripheral blood samples from patients with lung adenocarcinoma and healthy people were obtained clinically, and receiver operating characteristic (ROC) curves were drawn to clarify the sensitivity and specificity of B3GNT3 expression for the diagnosis of lung adenocarcinoma. Lung adenocarcinoma cells were cultured in vitro , the expression of B3GNT3 was knocked down by lentivirus infection. The expression of the apoptosis-associated genes was detected by reverse transcription-polymerase chain reaction (RT-PCR)., Results: The secreted protein B3GNT3 is significantly differentially expressed in the serum of patients with lung adenocarcinoma versus normal controls. Subgroup analysis according to lung adenocarcinoma clinical stage showed that the higher the clinical stage of lung adenocarcinoma was, the higher the B3GNT3 expression. Enzyme-linked immunosorbent assay (ELISA) revealed that B3GNT3 expression was significantly increased in the serum of patients with lung adenocarcinoma and significantly decreased after surgery. By inhibiting programmed cell death-ligand 1 (PD-L1), the level of apoptosis was significantly increased and the proliferative capacity was significantly inhibited. In contrast, the level of apoptosis was significantly increased and the proliferation ability was significantly inhibited after simultaneous overexpression of B3GNT3 and inhibition of PD-L1., Conclusions: High expression of the secreted protein B3GNT3 in lung adenocarcinoma is closely related to prognosis and can serve as a potential biological marker for the early screening of lung adenocarcinoma., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-22-1175/coif). All authors report that this study was funded by the Clinical Research Application Project, Zhejiang Provincial Health and Health Commission (No. 2022KY479) and Heilongjiang Provincial Department of Education Science and Technology Research Project (No. 2016-KYYWF-0887). The authors have no other conflicts of interest to declare., (2023 Journal of Thoracic Disease. All rights reserved.)

The survival of non-small cell lung cancer (NSCLC) patients has improved in the last decade as a result of introducing new therapeutics, such as immune checkpoint inhibitors, in the clinic. Still, some NSCLC patients do not benefit from these therapies due to intrinsic resistance or the development of acquired resistance and their malignant disease progresses. Further research on the molecular underpinnings of NSCLC pathobiology is required in order to discover clinically relevant molecular targets that regulate tumor immunity and to develop reasonable therapeutic combinations that will promote the efficacy of immune checkpoint inhibitors. Yes-associated Protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), the final effectors of the Hippo signaling transduction pathway, are emerging as key players in NSCLC development and progression. Herein, we overview studies that have investigated the oncogenic role of YAP/TAZ in NSCLC, focusing on immune evasion, and highlight the therapeutic potential of combining YAP/TAZ inhibitory agents with immune checkpoint inhibitors for the management of NSCLC patients.

Immunological evasion is one of the defining characteristics of cancers, as the immune modification of an immune checkpoint (IC) confers immune evasion capabilities to tumor cells. Multiple ICs, such as programmed cell death protein-1 (PD-1) and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), can bind to their respective receptors and reduce tumor immunity in a variety of ways, including blocking immune cell activation signals. IC blockade (ICB) therapies targeting these checkpoint molecules have demonstrated significant clinical benefits. This is because antibody-based IC inhibitors and a variety of specific small molecule inhibitors can inhibit key oncogenic signaling pathways and induce durable tumor remission in patients with a variety of cancers. Deciphering the roles and regulatory mechanisms of these IC molecules will provide crucial theoretical guidance for clinical treatment. In this review, we summarize the current knowledge on the functional and regulatory mechanisms of these IC molecules at multiple levels, including epigenetic regulation, transcriptional regulation, and post-translational modifications. In addition, we provide a summary of the medications targeting various nodes in the regulatory pathway, and highlight the potential of newly identified IC molecules, focusing on their potential implications for cancer diagnostics and immunotherapy.

Background: This study sought to depict the genomic landscape of patients with surgically resected lung squamous cell carcinoma (LUSC) and its relationship with clinical outcome indicators., Methods: We retrospectively collected the clinical data of 180 patients from the electronic medical records and applied targeted sequencing and immunohistochemistry (IHC) to depict the genomic landscape, including the tumor mutation burden (TMB), programmed cell death-ligand 1 (PD-L1), and cluster of differentiation CD8 + tumor-infiltrating lymphocytes (CD8 + TILs). And comparative analysis and survival analysis of these parameters were conducted to find prognostic factors for clinical outcome., Results: PD-L1+ tumor cells were observed in 75 (41.7%) of the patients, the median rate of CD8 + TILs was 11.5 [4, 24], and the median TMB was 9.4 (7.5-13.7) mutations per megabase (mut/Mb). Patched receptor 1 ( PTCH1 ) gene mutation frequency was significantly associated with CD8 + TILs density (12% vs. 1%; P=0.024). High PD-L1 expression and CD8 + TILs+ were significantly associated with longer disease-free survival (DFS), and a further subgroup analysis revealed that both were significantly correlated with the DFS of stage I/II patients but not stage III patients., Conclusions: The results suggest that only PTCH1 gene mutation frequency was correlated with CD8 + TILs density. Additionally, intense CD8 + TILs density and high PD-L1 expression were found to be associated with longer DFS. Our findings provide insights into the precise treatment strategy for surgically resected LUSC patients., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-22-630/coif). The authors have no conflicts of interest to declare., (2022 Journal of Thoracic Disease. All rights reserved.)

Over activation of immune checkpoint pathways assists tumor cells to escape the surveillance of immune system, resulting in generation and development of tumor. Drugs blocking immune checkpoints target lymphocyte receptors or their ligands to enhance endogenous antitumor activity by activating the immune system. The drugs targeting PD-1/PD-L1 axis have achieved favourable clinical efficacy, less and controllable toxicity and side effects. However, only a part of patients benefit from immunotherapy, so the problem of increasing the response rate of patients is on the agenda. Meanwhile, there are still some problems such as how to achieve the long-term response to most metastatic or non operative malignant tumors, and minimize the side effects of immune checkpoint inhibitor (ICI). Therefore, scientists are actively exploring methods, such as combining anti-PD-1 therapy with various traditional or newly developed therapeutic methods and building a tumor targeted drug delivery system to maximize the efficacy of drugs and reduce side effects. In this review, we summarized the related concepts and mechanism of PD-1 and its ligands PD-L1, and introduced certain drugs targeting PD-1/PD-L1 axis, their clinical effects and safety issues. Finally, a variety of combination therapies based on PD-1/PD-L1 and the application of different nanocarriers aiming at reducing non-targeting effect and improving the efficacy were discussed., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Challenges in medical care posed by rapid tumor progression, individualized responses to therapy, and the heterogeneous characteristics of breast cancer (BRCA) highlight the urgent need for new treatment strategies, as well as therapeutic and prognostic markers. Accumulating evidence has revealed that microRNAs broadly participate in carcinogenesis, but our understanding of the role of miR-93-5p in BRCA remains limited., Methods: The prognosis of miR-93-5p, programmed cell death-ligand 1 (PD-L1) and CCND1 were analyzed by datasets. Freshly excised breast cancer tissues (N=33) and adjacent noncancerous tissues (N=18) were collected to detect the expression of CCND1 and PD-L1 by immunohistochemistry (IHC). Quantitative real-time PCR (qRT-PCR) and Western blot were used to test the expression of miR-93-5p, PD-L1 and CCND1 after transfected mimics or inhibitors. Dual-luciferase reporter assay indicates the direct targeting between miR-93-5p and PD-L1., Results: Bioinformatics analysis demonstrated that miR-93-5p plays differential roles in various tumors, and further verification using qRT-PCR revealed that the expression levels of miR-93-5p were lower in MDA-MB-231 cells than in noncancerous breast cells. In addition, we confirmed that PD-L1 and CCND1 generated mutual effects, and miR-93-5p directly targets the PD-L1/CCND1 signaling pathway to influence their accumulation and distribution in the cell membrane, nucleus, and cytoplasm, mediating tumor progression and immune regulation in BRCA., Conclusions: Taken together, miR-93-5p could regulate tumorigenesis and tumor immunity by targeting PD-L1/CCND1 in BRCA and our research provides a rationale for therapy with miR-93-5p to overcome immune escape and improve risk stratification., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-22-97/coif). All authors report grants from the National Natural Science Foundation of China (No. 31670895); Key Scientific Research Projects of Higher Education Institutions of Henan Province of China (No. 16A35003); the Department of Science and Technology of Henan Province of China (No. 182102410007); and the Medical Science and Technology Project of Henan Province (No. LHGJ20200333). The authors have no other conflicts of interest to declare., (2022 Annals of Translational Medicine. All rights reserved.)

Cervical cancer is one of the most common in the female genital tract and remains a leading cause that threatens the health and lives of women worldwide, although preventive vaccines and early diagnosis have reduced mortality. While treatment by operation and chemoradiotherapy for early-stage patients achieve good outcomes, the great majority of cervical cancers caused by the human papilloma virus (HPV) make immunotherapy realizable for patients with advanced and recurrent cervical cancer. To date, some clinical trials of checkpoint immunotherapy in cervical cancer have indicated significant benefits of programmed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) inhibitors, providing strong evidence for PD-1/PD-L1 as a therapeutic target. In this review article, we discuss the role of PD-L1 and the application of PD-L1 inhibitors in cervical cancer, with the aim of providing direction for future research., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Anti-programmed cell death 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) immunotherapy has boosted the prognosis in advanced lung cancer. Meanwhile, accumulating cases showed the correlation between tuberculosis (TB) reactivation and anti-PD-1/PD-L1 immunotherapy. However, the safety and efficacy of anti-PD-1/PD-L1 immunotherapy for lung cancer complicated with TB infection could only be learned from real-world data., Methods: We retrospectively analyzed 562 patients with advanced lung cancer who received anti-PD-1/PD-L1 immunotherapy at Shanghai Pulmonary Hospital from 2015 to 2019, including 13 patients with TB infection. Besides, relevant literature reviews were performed online to analyze the safety and efficacy of immunotherapy and to explore the appropriate treatment strategies in this specific population., Results: In our cohort, the initiation of anti-PD-1/PD-L1 immunotherapy was from June 2015 to December 2019. Among them, 13 patients had TB infection prior to immunotherapy including 11 latent TB and 2 active TB, and all of them were treated with anti-PD-1 immunotherapy. Patients with active TB infection were treated with concurrent anti-TB and anti-PD-1 treatments, and the remaining received either mono-immunotherapy or combined immunotherapy. Neither reactivation of latent TB nor progression of active TB was monitored in our cohort during immunotherapy. Severe immune-related adverse events (irAEs) were diagnosed in two patients. Treatment strategies such as discontinuation of immunotherapy and administration of corticosteroids were provided timely, and one with latent TB infection got gradually improved, but the other one with active TB died quickly. The median progression-free survival (PFS) was 5.5 months for tumor immunotherapy in our cohort. However, the PFS of immunotherapy was merely 2.1 and 2.2 months in lung cancer patients with active TB infection., Conclusions: Immunotherapy is relatively safe for lung cancer patients complicated with previously treated latent TB, and the efficacy of immunotherapy in this specified population is not inferior to that in lung cancer patients without TB infection. TB screening before anti-PD-1/PD-L1 immunotherapy is strongly recommended, and irAEs should be monitored more cautiously in lung cancer patients with active TB infection., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/tlcr-21-524). CZ and YH serve as unpaid editorial board members of Translational Lung Cancer Research. The other authors have no conflicts of interest to declare., (2021 Translational Lung Cancer Research. All rights reserved.)

Background: Lung cancer is the most frequent cause of cancer-related deaths worldwide. The clinical development of immune checkpoint blockade has dramatically changed the treatment paradigm for patients with lung cancer. Yet, an improved understanding of PD-1/PD-L1 checkpoint blockade-responsive biology is warranted., Methods: We aimed to identify the landscape of immune cell infiltration in primary lung adenocarcinoma (LUAD) in the context of tumoral PD-L1 expression and the extent of immune infiltration ("hot" vs. "cold" phenotype). The study comprises LUAD cases ( n = 138) with "hot" (≥150 lymphocytes/HPF) and "cold" (<150 lymphocytes/HPF) tumor immune phenotype and positive (>50%) and negative (<1%) tumor PD-L1 expression, respectively. Tumor samples were immunohistochemically analyzed for expression of PD-L1, CD4, and CD8, and further investigated by transcriptome analysis., Results: Gene set enrichment analysis defined complement, IL-JAK-STAT signaling, KRAS signaling, inflammatory response, TNF-alpha signaling, interferon-gamma response, interferon-alpha response, and allograft rejection as significantly upregulated pathways in the PD-L1-positive hot subgroup. Additionally, we demonstrated that STAT1 is upregulated in the PD-L1-positive hot subgroup and KIT in the PD-L1-negative hot subgroup., Conclusion: The presented study illustrates novel aspects of PD-L1 regulation, with potential biological relevance, as well as relevance for immunotherapy response stratification.

To better understand the etiology of inflammatory breast cancer (IBC) and identify potential therapies, we studied genomic alterations in IBC patients. Targeted, next-generation sequencing (NGS) was performed on cell-free DNA (cfDNA) ( n = 33) and paired DNA from tumor tissues ( n = 29) from 32 IBC patients. We confirmed complementarity between cfDNA and tumor tissue genetic profiles. We found a high incidence of germline variants in IBC patients that could be associated with an increased risk of developing the disease. Furthermore, 31% of IBC patients showed deficiencies in the homologous recombination repair (HRR) pathway (BRCA1, BRCA2, PALB2, RAD51C, ATM, BARD1) making them sensitive to poly (ADP-ribose) polymerase (PARP) inhibitors. We also characterized the tumor-infiltrating lymphocytes (TILs) in tumor tissue biopsies by studying several markers (CD4, CD8, FoxP3, CD20, PD-1, and PD-L1) through immunohistochemistry (IHC) staining. In 7 of 24 (29%) patients, tumor biopsies were positive for PD-L1 and PD-1 expression on TILs, making them sensitive to PD-1/PD-L1 blocking therapies. Our results provide a rationale for considering PARP inhibitors and PD-1/PDL1 blocking immunotherapy in qualifying IBC patients.

Background: The aim of this study was to evaluate the safety and survival outcomes of anti-programmed cell death (PD)-1/programmed cell death-ligand 1 (PD-L1) monotherapy in patients with advanced non-small cell lung cancer (NSCLC) and different hepatitis B virus (HBV) infection status., Methods: Patients with advanced NSCLC and both chronic and/or resolved HBV infection who were treated with anti-PD-(L)1 monotherapy were retrospectively enrolled. The primary endpoint was the safety of PD-1/PD-L1 monotherapy, while the secondary endpoints included the survival outcomes., Results: Of the 62 eligible patients, 10 (16.1%) were hepatitis B surface antigen (HBsAg) positive [chronic hepatitis B (CHB) infection] and 52 (83.9%) were HBsAg negative and HBcAb positive [resolved hepatitis B (RHB) infection]; 42 (67.7%) patients had at least 1 treatment-related adverse event (AE), with 4 patients (6.5%) developing grade 3 AEs and 6 (9.7%) developing hepatic AEs. One CHB patient experienced HBV reactivation during anti-PD-1 immunotherapy due to the interruption of antiviral prophylaxis. The objective response rate and durable clinical benefit (DCB) rate were 17.7% and 29.0%, respectively. Median overall survival (OS) and progression-free survival (PFS) were 23.6 months [95% confidence interval (CI): 14.4-32.8] and 2.1 months (95% CI: 1.2-3.0), respectively. The DCB rate was significantly higher in the CHB group than in the RHB group (60% vs. 23.1%; P=0.048). Patients with CHB experienced a longer PFS (8.3 vs. 2.0 months; P=0.103) and OS (35.0 vs. 18.2 months, P=0.119) than did RHB patients., Conclusions: Anti-PD-(L)1 monotherapy was safe and effective in patients with NSCLC and HBV infection. This population should not be excluded from receiving immunotherapy in routine clinical practice or within clinical trials if HBV biomarkers are monitored and antiviral prophylaxis is properly used., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/tlcr-21-455). AR reports advisory board role for Astra Zeneca, MSD, and Novartis. RAS reports research grants from Astra-Zeneca, Boehringer Ingelheim, and advisory Board for Amgen, Astra-Zeneca, Bayer, BMS, Boehringer Ingelheim, Lilly, Merck, Novartis, Pfizer, Roche, Taiho, Takeda, Yuhan. EN received research funding from Roche, Pfizer, Merck-Serono, and Bristol Myers Squibb and received consultancy fees from Roche, BMS, MSD, Merck-Serono, Pfizer, Lilly, Amgen, Boehringer-Ingelheim, AstraZeneca, and Takeda. FP reports Consulting fees from MSD, Astrazeneca, Boehringer Ingheleim, Amgen and Pfizer. TM reports honorara for lecture and edcuational presentations as well as consultin fees from Astra Zeneca, Lilly, MSD, BMS. IJO received research funding from Roche and received consultancy fees from Roche, Ono, MSD, Pfizer, Boehringer-Ingelheim, AstraZeneca, Takeda. SW reports grant and personal fees from AstraZeneca and Boehringer Ingelheim, and personal fees from Chugai Pharma, Ono Pharmaceutical, Bristol-Myers, Eli Lilly, MSD, Taiho Pharmaceutical, Pfizer, Novartis and Daiichi Sankyo; outside the submitted work. The other authors have no conflicts of interest to declare., (2021 Translational Lung Cancer Research. All rights reserved.)

Background: A recent study showed that mucin-type sialylated O-linked glycans could induce the increased expression of PD-L1 via binding to Siglec receptors. However, the relationship between the expression of the mucin-type sialyl-Tn antigen (sTn) and PD-L1 remains unclear in breast cancer (BC). Therefore, we investigate the clinicopathological and prognostic effects of sTn expression and its relationship with PD-L1 expression in BC tissues., Methods: We retrospectively analyzed the clinical data of 380 invasive BC patients between January 2011 and January 2014. The last follow-up time was January 31, 2019 with a median follow-up of 62 months. The expression of the sTn antigen and PD-L1 in 380 tumor specimens was assessed by immunohistochemistry. Correlations between sTn/PD-L1 expression and clinicopathological features and prognoses were analyzed., Results: In BC tissues, the positive expression rate of PD-L1 (20.5%) was much lower than that of sTn (41.8%). Pearson's contingency analysis showed that sTn and PD-L1 expression in tumor tissues demonstrated a high correlation (P<0.001). High sTn expression was associated with negative ER expression (P<0.001), positive HER-2 status (P<0.001), advanced tumor stage (P<0.001), high density of CD8+ tumor-infiltrating lymphocytes (TILs) (P=0.028), and positive lymph node metastasis (P=0.002). Moreover, patients with concomitant high expression of both markers had the highest risk of relapse (P<0.001) and mortality (P<0.001). The multivariate Cox regression model revealed that positive sTn expression (HRos: 1.941, 95% CI: 1.168, 3.223, Pos=0.028; HRpfs: 1.739, 95% CI: 1.063, 2.847, Ppfs=0.010) and positive PD-L1 expression (HRos: 1.912, 95% CI: 1.138, 3.212, Pos=0.017; HRpfs: 1.863, 95% CI: 1.116, 3.110, Ppfs=0.014) were independent indicators for poor overall survival (OS) and progression-free survival (PFS), respectively., Conclusions: BC patients who expressed both sTn and PD-L1 had poorer survival. Therefore, combinational therapy with dual blockade might benefit BC patients with sTn(+)/PD-L1(+) expression, which requires further examination in future clinical trials., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/gs-21-83). The authors have no conflicts of interest to declare., (2021 Gland Surgery. All rights reserved.)

Background: Atezolizumab plus chemotherapy has been recommended as a first-line treatment option for patients with advanced non-small cell lung carcinoma (NSCLC) irrespective of programmed cell death-ligand 1 (PD-L1) expression. Currently, little is known about the efficacy and treatment-related adverse effects (TRAEs) of subtracting chemotherapy from the combination for patients with high PD-L1 expression. Thus, we performed an indirect comparison between atezolizumab plus chemotherapy and atezolizumab alone., Methods: A total of five eligible randomized controlled trials (RCTs) were identified from PubMed, EMBASE, and Cochrane Central controlled trial registries, using keywords including atezolizumab, PD-1, PD-L1, NSCLC, and RCT. The clinical outcomes of objective response rate (ORR), progression-free survival (PFS), OS, and TRAEs were extracted and evaluated. Using indirect analysis, the efficacy and TRAEs were compared between arm A (atezolizumab plus chemotherapy) and arm C (atezolizumab), linked by arm B (chemotherapy)., Results: Direct comparison revealed that both atezolizumab plus chemotherapy (HR 0.65, P = 0.003) and atezolizumab alone (HR 0.59, P = 0.010) significantly improved OS compared with chemotherapy. More importantly, the indirect comparison showed that atezolizumab plus chemotherapy was not superior to atezolizumab regarding OS (RR 1.10, P =0.695) and ORR (RR 1.11, P = 0.645). However, patients who received atezolizumab combined with chemotherapy experienced more ≥ grade 3 TRAEs (RR 4.23, P <0.001) and TRAEs leading to drug discontinuation (RR 3.60, P <0.001) than those treated with atezolizumab monotherapy., Conclusions: Atezolizumab monotherapy might be a better treatment option for patients with advanced NSCLC and high PD-L1 expression than atezolizumab plus chemotherapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Li, Lu, Yang, Zhang, Jin, Wang, Che, Li, Liu and Qu.)

The conventional etoposide-platinum (EP) regimen and adjuvant radiotherapy remain the gold-standard treatment for small cell lung cancer (SCLC). However, most patients already have multiple metastases when they are first diagnosed with SCLC. The objective response rate (ORR) and 1-year survival rate are low in these patients despite active radiotherapy and chemotherapy. SCLC is oncologically featured by the high tumor mutational burden (TMB) of multiple genes, which makes immunotherapy a possible new treatment strategy for SCLC. New data from the IMpower133 and CASPIAN trials will shed new light on the treatment of SCLC. In 2020, the results from the phase 3 CASPIAN trial have already suggested that programmed cell death-ligand 1 (PD-L1) inhibitors may represent breakthroughs in the management of SCLC. Here, we report a patient with extensive-stage SCLC (ES-SCLC) treated with first-line anti-PD-L1 immune checkpoint inhibitor (PD-L1 inhibitor) (i.e., durvalumab) combined with the EP regimen for 6 cycles. The patient consistently achieved partial response (PR) [nearly complete response (CR)], and no immune-related adverse events were noted during this period. The Karnofsky performance status (PS) score maintained at 1-2 points. We further review the history of SCLC treatment and elucidate the role of combination with immunotherapy in treating SCLC in the coming years.

Background: The aim of the present study was to analyze the association of programmed cell death-ligand 1 (PD-L1) and vascular endothelial growth factor receptor 2 (VEGFR2) expression levels with clinicopathological characteristics and survival to provide a treatment strategy for rectal cancer., Methods: Immunohistochemical staining of VEGFR2 and PD-L1 was carried out, and the association of PD-L1 and VEGFR2 expression levels with clinicopathological characteristics and survival were investigated in 77 pair-matched rectal cancer patients., Results: PD-L1 and VEGFR2 expression levels in surgical tumor tissues were higher than those in paired adjacent normal tissues, respectively (both P<0.05). The results of the 5-year overall survival (OS) analysis showed that patients with low VEGFR2 expression (66.7% vs. 43.5%, P=0.042) and high tumor PD-L1 expression (63.9% vs. 26.1%, P=0.001) in tumor tissues demonstrated significantly better OS. Patients with high TNM stage had poorer OS [hazard ratio (HR): 2.093, 95% confidence interval (CI): 1.027-4.087, P=0.030]. Similar results of poorer OS could be seen in patients with low tumor PD-L1 expression (HR: 3.365, 95% CI:1.747-6.481, P=0.005), as well as patients with high tumor VEGFR2 expression (HR: 0.418, 95% CI: 0.232-0.993, P=0.048)., Conclusions: The results indicated that tumor PD-L1 and VEGFR2 expression levels were associated with OS, and the combination of tumor PD-L1 and VEGFR2 levels might be an independent prognostic factor in rectal cancer., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tcr-20-3106). The authors have no conflicts of interest to declare., (2021 Translational Cancer Research. All rights reserved.)

Background: As a new strategy for advanced lung adenocarcinoma (LUAD), programmed cell death protein 1 (PD-1) pathway inhibitors have been used in clinic for several years. However, the roles of PD-1, programmed cell death-ligand 1 (PD-L1), and CD8A in LUAD are still unclear. In the study, we aimed to assess the correlation between the mRNA expression of these three factors and the clinical characteristics of LUAD, and to explore the influence of the PD-1/PD-L1/CD8A axis on the prognosis of LUAD., Methods: The mRNA expression data and clinical characteristics of LUAD patients were retrieved from The Cancer Genome Atlas (TCGA). The optimal cutoff value for PD-1, PD-L1, and CD8A was determined by Cutoff Finder. The chi-square test was used to compare categorical variables. The prognostic effects of variables were analyzed using the Kaplan---Meier method and the Cox proportional hazards model., Results: A total of 484 cases were enrolled in this study according to the selection process. The optimal cutoff values for identifying high/low mRNA expression were defined as 27.4 for PD-1, 29.41 for PD-L1, and 95.52 for CD8A. The high expression of PD-1 (P=0.015) and PD-L1 (P=0.027) was more frequent in women than in men. The high expression of PD-1 (P=0.003), PD-L1 (P=0.002), and CD8A (P=0.003) was associated with early T status, whereas CD8A showed a significantly higher expression in both the early stage (P=0.006) and early N stage groups (P=0.031). PD-1, PD-L1, and CD8A were significantly positively correlated among pairs (P<0.001). High expression of each of the three genes was associated with better prognosis (P=0.030 for PD-1, P=0.046 for PD-L1, P=0.019 for CD8A), although the relation did not reach statistical significance in the Cox regression hazards model., Conclusions: The study defined a group of cutoff values for PD-1, PD-L1, and CD8A to identify high and low mRNA expression in LUAD. The high expression of PD-1, PD-L1, and CD8A was associated with early T status, and CD8A showed significantly higher expression in both early stage and early N stage groups. Although the high expression of each of these three genes was associated with favorable overall survival (OS), they were not independent prognostic factors., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-20-6486). The authors have no conflicts of interest to declare., (2020 Annals of Translational Medicine. All rights reserved.)

Background: The aim of this study was to assess the prognostic value of CD8+ tumor infiltrating lymphocytes (TIL) combined with programmed cell death-ligand 1 (PD-L1) expression for patients with solitary colorectal cancer liver metastasis (SCLM) undergoing R0 resection., Methods: Patients undergoing curative hepatectomy for SCLM were reviewed. Immunohistochemical multiplex technique was used for quantifying CD8+ TIL, and immunohistochemical staining was used for assessing PD-L1 expression. The tumor immune microenvironment (TIME) was classified as strong for high CD8+ TIL and low PD-L1, weak for low CD8+ TIL and high PD-L1, and mild for the rest. Recurrence-free survival (RFS) and overall survival (OS) was compared between these groups., Results: Among the 94 patients included, a high CD8+ TIL and high PD-L1 expression was observed in 51 (54.3%) and 47 (50.0%) patients, respectively. Strong, mild, and weak TIME was observed in 24 (25.5%), 42 (44.7%), and 28 (29.8%) patients, respectively. Patients with a high CD8+ TIL had a significant longer RFS than patients with a low CD8+ TIL (3-year RFS rate, 71.6% vs. 55.3%, P=0.018). The 3-year RFS rate in the strong TIME group was significantly higher than that in the mild and weak TIME groups (89.5% vs. 71.7% and 28.8%, P<0.001), as was the 3-year rate of OS (93.8% vs. 81.8% and 61.6%, P<0.001). CD8+ TIL combined with PD-L1 expression showed better predicting accuracy for RFS than CD8+ TIL alone., Conclusions: The density of CD8+ TIL combined with PD-L1 expression in liver metastasis was a predictor of RFS for patients with SCLM undergoing R0 resection, and therefore can be used for guiding the postoperative treatment of these patients., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-20-2762a). All authors report grants from National Natural Science Foundation of China, grants from Natural Science Foundation of Guangdong Province, China, during the conduct of the study., (2020 Annals of Translational Medicine. All rights reserved.)

Background: It has been proven that the treatment window of small cell lung cancer (SCLC) is short, so it is vital to find other possible therapeutic targets. CD39 inhibits natural killer (NK) cells and promotes the occurrence and metastasis of tumors. There has been little research about the role of CD39 in SCLC, so we explored the correlation between CD39 and other surface antigens, and its association with survival in SCLC., Methods: This study included 75 patients with SCLC from Shanghai Pulmonary Hospital. After paraffin embedding and sectioning, immunohistochemistry (IHC) was applied. Then we identify cutoff value for CD39 and other surface antigens based on the analysis of ROC curve in RFS by SPSS. All statistical analyses were based on SPSS and Graphpad Prism8. Chi-square test, Kendall's tau-b correlation analysis, Logistic regression analysis, Kaplan-Meier method, univariate and multivariate Cox regression analysis were conducted. In all analyses, P = 0.05 distinguished whether they had statistical significance., Results: Of the 75 SCLC patients enrolled in this study, 61.33% positively expressed CD39. A correlation between CD39 and programmed cell death-ligand 1 (PD-L1) (P=0.007), CD3 (P<0.001), CD4 (P<0.001), CD8 (P<0.001), and forkhead box P3 (FOXP3) (P<0.001) on tumor-infiltrating lymphocytes (TILs) was identified by correlation analysis and logistic regression analysis. Based on Kaplan-Meier survival analysis, we found that CD39 affected relapse-free survival (RFS) [negative vs. positive, 95% confidence interval (CI): 0.2765-0.9862, P=0.0390]. SCLC patients with high-expressed CD39 and low-expressed PD-L1 had poor prognosis (P<0.001). Positive expression of CD39 and negative expression of CD3, CD4, CD8, and FOXP3 also indicated shorter RFS (P=0.0409). Univariate and multivariate Cox regression analysis was performed to confirm the factors that influenced RFS., Conclusions: CD39, programmed cell death-1 (PD-1), and PD-L1 expressed on TILs but not on tumor cells. CD39 has a significant association with PD-L1, CD3, CD4, CD8, and FOXP3 on TILs. The positive expression of CD39 predicts poor prognosis. SCLC patients with low expression of CD39 combined with high expression of PD-L1 or CD3, CD4, CD8, and FOXP3 have a more favorable prognosis., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tlcr-20-798). The authors have no conflicts of interest to declare., (2020 Translational Lung Cancer Research. All rights reserved.)

Purpose: To determine whether distinct tissue immune microenvironments differentially impact on clinical outcome in non-small cell lung cancer (NSCLC), an extended analysis of PD-1/PD-L1 and Tumor Infiltrating Lymphocytes (TILs) was performed. Materials and Methods: 1016 NSCLC mRNA-sequence samples from The Genome Data Analysis Center (TCGA) and 275 NSCLC mRNA-microarray samples from Gene Expression Omnibus (GEO) were included as testing cohort and validation cohort respectively. Enrichment scores of CD8+ T cells' metagene were used for quantifying its infiltrating density. Based on the median values of CD8+ T cell density and PD-1/PD-L1 mRNA expression, the samples were classified into four Tumor Immune Microenvironment types (TIMTs). Overall survival, as well as clinicopathological features, mutational profiles, mismatch repair score etc. were compared across the four types. Results: Neither PD-1 expression nor PD-L1 expression was associated with outcome in the overall NSCLC. Classification of TIMT based on PD-1/PD-L1 and CD8+ TIL could efficiently classify patients of different survival in ADC but not SCC, with the best overall survival achieved in TIMT3 (high CD8+ TIL and low PD-1/PD-L1), whereas TIMT2 (low CD8+ TIL and high PD-1/PD-L1) manifested the worst outcome. TIMT classification based on PD-1/ CD8+ TIL could better stratify patient of different prognosis than PD-L1/ CD8+ TIL based classification. EGFR wide type and IFNγ overexpression were associated with TIMT4 (high PD-1/PD-L1 and high CD8+ TIL), whereas tumor mutational burden (TMB) manifested no significant difference across four TIMTs. Conclusion: The classification of tumors into four microenvironment subtypes based on PD-1/PD-L1 status and CD8+ TIL is an appropriate approach to stratify patients of different clinical outcome and better guide the practical use of immunotherapy., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

Background: Pulmonary neuroendocrine tumor (NET) occurs with 20% of all lung cancers, and there are a limited number of literatures about the molecular aberrations, treatment and prognosis; especially in resected cases, as the operation indication for large cell neuroendocrine carcinoma (LCNEC) and small cell lung carcinoma (SCLC) is rare due to their aggressive behaviors. We investigated the relationship between postoperative survival and molecular expression patterns of pulmonary NET to establish a more effective treatment strategy., Methods: In the present study, the curative surgical resection of pulmonary NET was reviewed retrospectively. A total of 105 patients with pulmonary NET, who underwent complete resection between 1978 and 2016, were subjected to analysis with respect to histological characterization and clinical behaviors of pulmonary NET using immunohistochemistry (IHC) of neuroendocrine markers and programmed cell death-ligand 1 (PD-L1)., Results: The pathological types included 67 SCLC, 18 LCNEC, 14 typical carcinoids (TCs) and 6 atypical carcinoids (ACs). The ACs had significantly worse prognosis than TCs. PD-L1 expression ratio in SCLC/LCNEC/TC/AC was 26.1%/50%/15.4%/20%, respectively. However, it was not significantly correlated with each prognosis. Therefore, the SCLC patients were analyzed, the overall 5-year survival of SCLC patients was found to be 47.3%. In the univariate analysis of the molecular expression of SCLC, neuroendocrine markers such as chromogranin-A (CGA) and synaptophysin (SYN) showed poor prognosis, albeit without significant differences., Conclusions: The neuroendocrine markers such as CGA and SYN might assist the prediction of prognosis and probably influence the decision for adjuvant chemotherapy or follow-up intervals after surgery in SCLC patients; however additional studies are essential., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Cancer immunotherapy, which could utilize the host's immune system to kill tumor cells, has great potential in long-term inhibition of tumor growth and recurrence compared to chemotherapy and radiotherapy. As we know, tumors exhibit powerful adaption to escape the destruction of immune system at the late stage of diseases due to overactivation of immune checkpoint pathways which function as natural "brakes" for immune responses. The newly emerging immune checkpoint inhibitors are regarded as the breakthrough for cancer immunotherapy as they can re-boost the host's immune system by restoring T cells function and promoting cytotoxic T lymphocytes (CTLs) responses. However, there is still scope for improvement in enhancing the clinical efficacy and reducing side effects of these immune modulators. In this review, we mainly introduce the basic mechanisms of the immune checkpoint pathways and outline the recent successes of immune checkpoint blockade (ICB) therapy in combination with nanoparticle delivery system. Furthermore, the underexplored potential in application of nanotechnology to enhance the efficacy of immune checkpoint therapy and overcome the limits of immune checkpoint inhibitors is also discussed., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Little is known about immune-related prognostic factors in patients with nasopharyngeal carcinoma (NPC)., Methods: We retrospectively reviewed 66 patients with NPC. Epstein-Barr virus (EBV) status, programmed cell death-ligand 1 (PD-L1) expression, and tumor-infiltrating lymphocyte (TIL) densities were analyzed, and a prognostic evaluation of these immune-related parameters was performed., Results: The multivariate analyses demonstrated that CD8-positive TIL density but not PD-L1 expression on tumor cells or immune cells was a significant predictive factor for progression-free survival (PFS) and overall survival (OS). Subgroup analyses demonstrated that a positive PD-L1 expression on tumor cells in combination with a higher CD8-positive TIL density was significantly associated with favorable prognosis, whereas positive PD-L1 expression on tumor cells with lower CD8-positive TIL density was associated with worse prognosis., Conclusion: Our results suggest that PD-L1 expression on tumor cells in combination with CD8-positive TIL density could be a useful predictive biomarker for risk stratification in patients with NPC., (© 2018 Wiley Periodicals, Inc.)

Objectives: Expression of programmed cell death-ligand 1 (PD-L1) has been associated with clinical outcome of programmed cell death-1 (PD-1) pathway blockade in non-small cell lung cancer (NSCLC). The PD-L1 IHC 22C3 pharmDx assay, the only companion diagnostic for pembrolizumab therapy, has revealed that ∼30% of all NSCLCs express PD-L1 at a high level. The frequency of high PD-L1 expression in NSCLCs with known driver oncogenes has remained unclear, however., Materials and Methods: We retrospectively evaluated PD-L1 expression with the 22C3 assay in tumor tissue of 80 lung adenocarcinoma patients including 71 with EGFR mutations and 9 with ALK rearrangements, all of whom were treated with corresponding tyrosine kinase inhibitors (TKIs)., Results: Of the 80 tumors analyzed, 26 (32.5%) had a PD-L1 tumor proportion score (TPS) of 1%-49% and 9 (11.3%) had a PD-L1 TPS of ≥50%; 35 (43.8%) thus had a PD-L1 TPS of ≥1%. Of the 71 tumors with EGFR mutations, 23 (32.4%) had a PD-L1 TPS of 1%-49% and 7 (9.9%) had a PD-L1 TPS of ≥50%. A PD-L1 TPS of ≥1% was not associated with any clinical characteristic examined. Progression-free survival on initial TKI treatment was significantly poorer for patients with a PD-L1 TPS of ≥1% than for those with a PD-L1 TPS of <1% (p = .016)., Conclusions: A subset of patients with EGFR mutations or ALK rearrangements had a PD-L1 TPS of ≥50%. Prospective studies are thus warranted to examine the efficacy of PD-1/PD-L1 inhibitors in such patients., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Aberrant expression of programmed cell death-ligand 1 (PD-L1) and protein 53 (P53) has been observed in various malignancies, and recently, the mechanism of PD-L1 regulation by P53 has been elucidated. We aimed to explore possible correlations between PD-L1 and P53 expression and the prognosis of patients with resected pulmonary lymphoepithelioma-like carcinoma (LELC)., Methods: A total of 67 consecutive patients with primary pulmonary LELC who underwent radical resection from January 2003 to December 2014 were enrolled in our study. Membranous PD-L1 and nuclear P53 expression were detected by immunohistochemical staining (IHC)., Results: Positive expression of PD-L1 in tumor cells (TCs), PD-L1 in tumor-infiltrating lymphocytes (TILs) and P53 was investigated in 44 patients (65.7%), 37 patients (55.2%), and 34 patients (50.7%), respectively. Using univariate and multivariable analysis, both PD-L1 (+) in TCs and P53 (+) were observed to be significantly independent prognostic factors associated with longer disease-free survival (DFS, P=0.037 and 0.039, respectively), along with early stage LELC (P=0.037), but had no association with overall survival (OS) (P>0.05). In the P53 (+) group, the rate of patients with PD-L1 (+) in TCs was significantly higher than in the P53 (-) group (85.3% vs. 45.5%, P=0.001). In addition, among the 45 patients who underwent adjuvant chemotherapy, DFS was significantly longer in patients with either PD-L1 (+) in TCs or P53 (+) (P=0.036 and 0.044, respectively)., Conclusions: PD-L1 and P53 may be potential therapeutic targets for primary pulmonary LELC. PD-L1 (+) in TCs and P53 (+) were reliable predictors for longer DFS and benefits from adjuvant therapy in resected cases. Routine detection of these two indices in lung LELC may be warranted., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Immunotherapy is reportedly effective in colorectal cancers (CRCs) with high microsatellite instability (MSI-H); however, the specific cell types that respond to immune checkpoint therapy are unclear. Herein, we aimed to examine the expression of programmed cell death-ligand 1 (PD-L1) and related proteins in MSI-H and microsatellite-stable (MSS) CRCs to investigate the immune microenvironment at the tumor's invasive front. The MSI status was retrospectively assessed in 499 patients undergoing surgical resection of primary CRC; of these, 48 were classified as MSI-H. Propensity score matching was performed, and tissues from 36 and 37 patients with MSI-H and MSS CRCs, respectively, were immunohistochemically evaluated for PD-L1, PD-1, CD8 and CD68. PD-L1 expression was evaluated separately for tumor cells (PD-L1 [T]) and tumor-infiltrating myeloid cells in the stroma (PD-L1 [I]). PD-L1 (T) was positive in only 5.4% and 36.1% of MSS and MSI-H CRCs, while PD-L1 (I) was positive in 27% and 72.2% of these CRCs, respectively. The PD-L1 (T) and PD-L1 (I) expression levels in MSI-H CRCs significantly correlated with poor differentiation, lymphatic invasion and vascular invasion (p < 0.05), and with early-stage adenocarcinoma and high budding grade (p < 0.05), respectively. Significantly more PD-L1 (I), CD8-positive cells and CD68-positive macrophages were present at the invasive front than in the central tumor in MSI-H CRCs (p < 0.005). PD-L1 was expressed on both tumor cells and CD68/CD163-positive (M2) macrophages at the invasive front of MSI-H CRCs. In conclusion, PD-L1-positive tumor cells and M2-type tumor-associated macrophages may contribute to tumor invasion and immune escape at the invasive front., (© 2017 UICC.)

Background: The programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) pathway inhibits the activation of T cells and plays a crucial role in the negative regulation of cellular and humoral immune responses. Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoid malignancy in adults. In the present study, we aimed to detect the expression of PD-L1 in DLBCL and to analyze its relationship with prognosis., Methods: We reviewed medical records of 204 newly diagnosed DLBCL patients in Sun Yat-sen University Cancer Center between October 2005 and August 2012. The expression of PD-L1 in tumor tissues from these 204 patients was detected using immunohistochemical (IHC) assay. The expression of anaplastic lymphoma kinase (ALK), CD5, CD30, and C-Myc in tumor specimens from 109 patients was detected using IHC, and Epstein-Barr virus (EBV)-encoded RNAs (EBERs) were detected using fluorescence in situ hybridization. The Spearman method was used for correlation analysis. The Kaplan-Meier method with log-rank test was used for univariate analysis. Cox proportional hazards model was used for multivariate analysis., Results: Of the 204 patients, 100 (49.0%) were PD-L1-positive in tumor cells and 44 (21.6%) were PD-L1-positive in tumor microenvironment. PD-L1 expression in tumor cells and tumor microenvironment were more common in the non-germinal center B-cell-like (GCB) subtype than in the GCB subtype (P = 0.02 and P = 0.04). Patients with PD-L1 expression in tumor microenvironment were more likely to be resistant to first-line chemotherapy when compared with the patients without PD-L1 expression in tumor microenvironment (P = 0.03). PD-L1 expression in tumor microenvironment was negatively correlated with C-Myc expression (r = - 0.20, P = 0.04). No correlations were detected between PD-L1 expression and the expression of ALK, CD5, and CD30 as well as EBERs. The 5-year overall survival (OS) rates were 50.0% and 67.3% in patients with and without PD-L1 expression in tumor cells (P = 0.02). PD-L1 expression in tumor cells was an independent risk predictor for OS (P < 0.01)., Conclusions: PD-L1 expression is more common in the non-GCB subtype than in the GCB subtype. PD-L1 expression in tumor microenvironment has a negative correlation with C-Myc. PD-L1 positivity predicts short survival in DLBCL patients. For patients with PD-L1 expression, more strategy such as anti-PD-L1 antibody treatment should be recommended.

The immune system affects all phases of tumor growth from initiation to progression and dissemination. Tumor-infiltrating lymphocytes (TILs) are mononuclear immune cells that infiltrate tumor tissue. Several retrospective studies have suggested the potential of TILs as a prognostic as well as predictive factor of chemotherapy in some breast cancers. On the other hand, programmed cell death protein-1 (PD-1) and programmed cell death-ligand 1 (PD-L1) eliminate T cell activation in various types of cancers. Prospective trials to evaluate the efficacy of antibody agents to PD-1 and PD-L1 are ongoing in patients with breast cancer. The findings of these studies appear to support the potential of immune checkpoint inhibitors targeting the PD-1/PD-L1 axis in triple negative breast cancer. Further studies are needed in order to confirm previous findings on TILs and promote the development of new immune therapy approaches for breast cancer patients. Furthermore, the search for TILs will soon be introduced into actual clinical practice, for which the standardization of evaluation methods and establishment of a simple evaluation method are expected.

Background: Nivolumab offers a superior survival benefit over docetaxel in patients with advanced, previously treated non-small-cell lung cancer (NSCLC). An association between programmed cell death ligand-1 (PD-L1) expression and the efficacy of nivolumab has been reported in many studies. However, the association between the clinical parameters and efficacy of nivolumab remains unclear in advanced NSCLC patients., Results: Among 124 patients, 108 (88%) were performance status (PS) 0 to 1. PD-L1 expression was assessed in 89 patients, with 51 (57%) patients having PD-L1 positive expression. In all patients, the objective response rate (ORR) in patients with elevated CRP levels (≥ 1 mg/dl) was significantly worse than those without elevated CRP levels (< 1 mg/dl) (8.3 vs 23.4%, p = 0.0180). The PS (≥ 2), smoking index (< 400), CRP levels (≥ 1 mg/dl) and LDH (≥ 245 IU/L) were significantly associated with a shorter PFS and OS in patients treated with nivolumab. Multivariate analyses showed that the PS (≥ 2), smoking index (< 400), CRP levels (≥ 1 mg/dl) and LDH (≥ 245 IU/L) and PD-L1 expression were significant factors associated with a longer PFS of nivolumab., Materials and Methods: We retrospectively analyzed 124 patients who received nivolumab as a subsequent treatment. The patient characteristics, laboratory data at baseline (C-reactive protein [CRP] and lactate dehydrogenase [LDH]), PD-L1 expression, nivolumab response, progression-free survival (PFS), and overall survival (OS) were evaluated., Conclusions: Clinical parameters, such as PS, serum CRP, serum LDH, and smoking status, were significantly associated with the response duration and survival in patients treated with nivolumab., Competing Interests: CONFLICTS OF INTEREST None.

Objectives: Locally recurrent or metastatic nasopharyngeal cancer (NPC) remains an important challenge, with more effective and durable therapeutic options needed. Cancer immunotherapy, and in particular therapies that target the PD-L1/PD-1 immune checkpoint pathway, may provide new options to treat NPC patients. This study evaluated PD-L1 and CD8 expression levels and the respective associations with clinical and histopathological characteristics of patients with NPC., Materials and Methods: Diagnostic tumour biopsies were obtained before radical radiotherapy with or without chemotherapy from 161 patients with NPC. These biopsies were analysed for PD-L1 expression levels on tumour cells (TC) and tumour-infiltrating immune cells (IC), and for CD8 T-cell infiltration. Results were correlated with baseline characteristics and clinical outcomes with standard-of-care treatment regimens. Additionally, pre- and post-treatment-paired tumour samples were analysed (n=146)., Results: 75% of tumours expressed PD-L1 on IC and 24% on TC. Baseline clinical characteristics of stage, sex and age did not correlate with PD-L1 expression. Additionally, overall survival and progression-free survival of standard-of-care treatment did not correlate with baseline PD-L1 expression. CD8 levels did correlate with clinical outcomes; however, results were confounded by other baseline characteristics. After treatment, PD-L1 expression dropped a median of 1.5% on IC and a median of 2.75% on TC. Median CD8 expression dropped 1.9%., Conclusions: Majority of NPC biopsy samples demonstrated PD-L1 expression on ⩾1% of IC, with fewer expressing PD-L1 on TC. In contrast to previous smaller studies, no prognostic value was observed for PD-L1 expression levels in patients with NPC., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) pathway-targeted immunotherapy has become the standard option of care in the management of lung cancer. The expression of the PD-L1 protein in lung cancer is expected to be a prognostic factor or to predict the response to PD-1-blocking antibodies. However, the association between PD-L1 positivity and the clinicopathological features and patient outcomes in lung squamous cell carcinoma (SCC) remains unclear because the definitive cut-off value for the expression of PD-L1 protein remains to be established., Materials and Methods: The expression of PD-L1 protein in 205 surgically resected primary lung SCC patients was evaluated by immunohistochemistry with the antibody clone SP142. We generated a histogram to show the proportion of PD-L1-positive carcinoma cells, and set the cut-off values as 1%, 5%, 10% and 50%. Moreover, we examined the proliferative capacity of these tumors using Ki-67 immunohistochemistry., Results: The samples from 106 (51.7%), 72 (35.1%), 61 (29.7%) and 37 (18.0%) patients were positive for the expression of PD-L1 protein at cut-off values of 1%, 5%, 10% and 50%, respectively. Fisher's exact test showed that, for almost all of the factors, PD-L1 positivity was not associated with the clinicopathological features with any of the four cut-off values. Univariate and multivariate survival analyses revealed that the PD-L1-positive patients only had a poorer prognosis than the PD-L1-negative patients at the 1% cut-off value. The Ki-67 labeling index in the PD-L1-positive patients was higher than that in the PD-L1-negative patients., Conclusions: The expression of PD-L1 protein was associated with a poor prognosis in lung SCC patients. The 1% cut-off value for PD-L1 might become a better predictive marker than the other cut-off values., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Lung cancer is the leading cause of death cancer related worldwide. The standard therapies have unmet medical needs both due to the limited activity and relevant toxicity of platinum-based chemotherapy and to the low frequency of specific alterations required to use targeted therapies. Immune checkpoint inhibition due to restoring the immune system's capacity to eradicate tumors is undergoing in extensive investigation in non-small cell lung cancer (NSCLC) as a new treatment approach. Programmed cell death protein-1 (PD-1) and its ligand, programmed cell death-ligand 1 (PD-L1) have recently led to significantly and durable improvements in the clinical outcome of several kind of tumors including lung cancer. Pembrolizumab, approved by the U.S. FDA for the treatment of advanced NSCLC progressed after other therapies and with expression of PD-L1, has demonstrated durable response and prolonged overall survival (OS) especially in patients with high PD-L1 expression. Further investigation are needed to improve treatment outcomes through combination of immunotherapy or combined with other targeted therapies.

Background: Observational studies on the prognostic role of programmed cell death-ligand 1 (PD-L1) in non-small cell lung cancer (NSCLC) are controversial., Methods: To clarify the impact of PD-L1 in NSCLC survival, we performed this meta-analysis that included eligible studies. The combined hazard ratios (HR) and their corresponding 95% confidence intervals (CIs) were calculated in terms of overall survival., Results: A total of five studies with 877 patients were evaluable for this meta-analysis. Our results suggested that PD-L1 overexpression had a poor impact on survival of patients with NSCLC, the HR (95% CI) was 1.43 (1.24-1.63) overall, 1.51 (1.24-1.7954) in Asian patients, 1.35 (1.08-1.63) in non-Asian patients. Moreover, there was no heterogeneity between the studies., Conclusions: PD-L1 overexpression indicates a poor prognosis for patients with NSCLC.