Development in immunotherapy of lung cancer / 中国胸心血管外科临床杂志

@#Lung cancer is the leading cause of cancer-related deaths worldwide. Although improvement has been achieved in platinum-based chemotherapy and tyrosine kinase inhibitors-based molecular targeted therapy, they still have limitations. Immunotherapy has recently emerged as a very effective new treatment, and there is now growing enthusiasm in cancer immunotherapy worldwide. We summarized the effects of immune checkpoint inhibitors in clinical trials, and the current status and progress of anti programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) agents in lung cancer treatment. Attention has been paid to finding out the factors which influence the therapeutic effect of anti-PD-1/PD-L1 therapy and reducing the occurrence of adverse events.

Correlation between the expression of PD-L1 and dMMR related proteins in follicular thyroid carcinoma tissues and its clinical significance / 中国肿瘤生物治疗杂志

@#[Abstract] Objective: To investigate the correlation between PD-L1 expression and dMMR related proteins in follicular thyroid carcinoma tissues and its clinical significance. Methods: The postoperative paraffin-embedded tissue samples from 60 patients with thyroid follicular carcinoma were collected from the Second Affiliated Hospital of Fujian Medical University during January 2015 and June 2020. The collected samples were re-confirmed as thyroid follicular carcinoma tissues by Hematoxylin-eosin staining. The expression of PD-L1 and four homologous proteins encoded by four genes (MLH1, MSH2, MSH6, PMS2) in MMR system were detected by immunohistochemistry in the cancer and paracancerous tissues. The relationship between the expression of PD-L1 and depletion of MMR related proteins in thyroid follicular carcinoma tissues and its clinical significance were analyzed. Results: The positive expression rate of PD-L1 was significantly higher in the follicular thyroid carcinoma tissues than that in paracancerous tissues [63.3%(38/60) vs 11.7%(7/60), P<0.05]. The expression of PD-L1 was significantly correlated with tumor diameter, extrathyroidal infiltration, vascular invasion and recurrence (all P<0.05). In the cancer tissue specimens from 60 patients, 24 (40.0%) had expression of four MMR related proteins, which were pMMR tumors, and 36 (60.0%) had depletion of one or more MMR related proteins, which were dMMR tumors. The dMMR-type thyroid follicular carcinoma was significantly correlated with the status of lymph node metastasis and tumor staging (all P<0.05). PD-L1 was positively correlated with the incidence of dMMR, and PD-L1 was an independent risk factor for disease recurrence, while dMMR was associated with a better prognosis. Patients with PD-L1+/pMMR type were associated with higher tumor malignancy, while patients with PD-L1+/dMMR type were not associated with tumor pathological features but may easily benefit from immunotherapy. Conclusion: Positive PD-L1 expression and dMMR highly occur in follicular thyroid carcinoma. PD-L1 is associated with the increased tumor invasion and is an independent risk factor for disease recurrence, while dMMR is an early molecular event in the development of thyroid follicular carcinoma and is associated with better prognosis of patients.

The Expression of Programmed Death Ligand-1 within Stages of Oral Squamous Cell Carcinoma: Immunohistochemical Analysis

Background: Oral squamous cell carcinoma is prevalent in South Asian countries with rising cases of its incidence and mortality. Despite advancements in treatment, survival and recurrence rates are poor. Immunotherapy is a novel therapeutic modality in immunooncology. Immune checkpoint proteins are under investigation for clinical implications amongst which Programmed Death Ligand-1 has shown valuable results in certain malignancies. Aims: To determine the immunohistochemical expression of Programmed Death Ligand-1(PD-L1) in oral squamous cell carcinoma and to find an association of Programmed Death Ligand-1 with stage and clinicopathological parameters of oral squamous cell carcinoma.Study Design:Cross-sectional study.Place and Duration of Study:Ziauddin Medical University, Karachi, 1 Year duration during 2018-2019.Methods: A total number of140 biopsy confirmed cases of oral squamous cell carcinoma were recruited in the study. Immunohistochemical expression of Programmed Death Ligand-1 was evaluated and associated with the clinicopathological parameters of oral squamous cell carcinoma (OSCC). The data was statistically analyzed through Descriptive statistics and Chi square test by using SPSS v.20.Results: Out of 140 participants, 74% were males (n=103) and 26% were females (n=37). Programmed Death Ligand-1 positivity was observed in 62.1% of cases (n=87). The Mean age of the participants was 48.91 ± 11.7 years. The most common site of cancer involvement was buccal mucosa and majority of participants were habitual of consuming chewable products i.e. Pan, Gutka and betel nut (89; 64%). Stage III and IV tumours comprised a major portion of cases in our study.(52; 37%), (56; 40%).A statistically significant p-value was noted for the association of Programmed Death Ligand-1 with stage II and IV tumours. (P-values: 0.029, 0.001)The association of Programmed Death Ligand-1 with other variables such as age, gender, ethnicity, sites or habits was not statistically significant.Conclusion:This study concludes that the statistical significance of Programmed Death Ligand-1 expression with tumour stage is suggestive of worsening prognosis and might have detrimental effects as tumour progresses in advanced stage. Programmed Death Ligand-1 positivity in patients having oral squamous cell carcinoma could be useful in future research in the light of cancer immunotherapy which has shown success in oncology.

knocking out mediated by CRISPR-Cas9 genome editing for PD-L1 attenuation and enhanced antitumor immunity

Blocking the programmed death-ligand 1 (PD-L1) on tumor cells with monoclonal antibody therapy has emerged as powerful weapon in cancer immunotherapy. However, only a minority of patients presented immune responses in clinical trials. To develop an alternative treatment method based on immune checkpoint blockade, we designed a novel and efficient CRISPR-Cas9 genome editing system delivered by cationic copolymer aPBAE to downregulate PD-L1 expression on tumor cells specifically knocking out Cyclin-dependent kinase 5 () gene . The expression of PD-L1 on tumor cells was significantly attenuated by knocking out , leading to effective tumor growth inhibition in murine melanoma and lung metastasis suppression in triple-negative breast cancer. Importantly, we demonstrated that aPBAE/Cas9-Cdk5 treatment elicited strong T cell-mediated immune responses in tumor microenvironment that the population of CD8 T cells was significantly increased while regulatory T cells (Tregs) was decreased. It may be the first case to exhibit direct PD-L1 downregulation CRISPR-Cas9 genome editing technology for cancer therapy. It will provide promising strategy for preclinical antitumor treatment through the combination of nanotechnology and genome engineering.

Establishment of a lung cancer mouse model with humanized immunity and its role in efficacy evaluation of programmed death-1 inhibitors / 上海交通大学学报（医学版）

Objective:To establish a lung cancer mouse model with humanized peripheral blood mononuclear cells (PBMC) expressing programmed death-ligand 1 (PD-L1), and study the role of the model in evaluating the efficacy of programmed death-1 (PD-1) inhibitors. Methods:Fresh biopsy tissue samples or tumor cells in malignant pleural effusion from the patients with advanced non-small cell lung cancer were inoculated subcutaneously in CB17-SCID mice to establish patient-derived xenograft (PDX) models. The expression of PD-L1 in PDX models was detected by immunohistochemistry. The mature human PBMC and PDX model tumor cells were mixed and then inoculated into NCG mice to establish a PDX model of lung cancer with humanized immunity, on which the efficacy of PD-1 inhibitor was verified. Results:Among the PDX models established by 16 clinical samples, 2 were strongly positive for PD-L1, 4 were positive, and the rest were negative. In the PDX model with strongly positive PD-L1, the tumor growth inhibition rate of cindilimab, an inhibitor of PD-1, was 82.6%, 21 days after the initial administration; in the PDX model with negative PD-L1, the inhibitor of PD-1 showed no antitumor activity. Conclusion:A PD-L1-expressing lung cancer mouse model with humanized immunity is successfully established and the efficacy of PD-1 inhibitor can be evaluated on the model.

Research progress of PD-1/PD-L1 in head and neck squamous cell carcinoma / 中国肿瘤临床

Head and neck squamous cell carcinoma (HNSCC) is a kind of malignant tumor characterized by metastasis and local invasion. Its recurrence rate is high after surgery and radiotherapy, and the prognosis and quality of life are poor. In recent years, programmed death-1 (PD-1) inhibitors have been recommended in National Comprehensive Cancer Network (NCCN) guidelines for the treatment of recurrent, unresectable, and metastatic HNSCC, and their efficacy has been remarkable. PD-1 inhibitors constitute a new treatment for the patients with advanced HNSCC who are refractory to platinum-based chemotherapy and can increase the probability of surgical resection, reduce the risk of postoperative dysfunction, and improve the survival and quality of life. This article reviews the structure and mechanism of the PD-1/PD-L1 immunocheckpoint, as well as research progress on its inhibitors in the treatment of HNSCC.

Charaoteristics and clinical significance of immune microenvironment in nonsmall cell lung cancer tissues / 中国肿瘤生物治疗杂志

@# Objective: To investigate the characteristics and clinical significance of the immunomicroenvironment typing based on the expression of programmed death-ligand 1 (PD-L1) and the infiltration of CD8+ T cells in the stroma in patients with non-small cell lung cancer (NSCLC). Methods: Paraffin tissue specimens and relevant clinicopathological data of 74 NSCLC patients admitted to our hospital from January 2016 to July 2018 were collected.All patients received EGFR gene test, and none received radiotherapy, chemotherapy or targeted therapy. Immunohistochemistry was used to detect the expression of PD-L1 in tissues and the infiltration of CD8+T cells in interstitium, and the relationship between PD-L1, CD8+T cells, and the immune microenvironment typing based on both, and the pathological parameters and the survival of patients was analyzed. Results: PD-L1 expression in the primary tumor of NSCLC patients showed statistical differences in gender, pathological type, smoking history, EFGR gene mutation status ( P <0.05). The infiltration of CD8+ T lymphocytes in tumor microenvironment showed statistically significant differences in different TNM stage and lymph node metastasis ( P <0.05), PD-L1 expression was significantly correlated with EGFR mutation ( P =0.000), while CD8+T lymphocyte infiltration was not correlated with EGFR mutation ( P =0.605). The immunomicroenvironment of EGFR wild-type patients was mainly (CD8+ PD-L1+) (type I), and the mutants were mainly (CD8-PD-L1-) (type II) and (CD8+PD-L1-) (type IV). The distribution of immune microenvironmental typing in each group with different EGFR mutation, smoking history and pathological differentiation degree was significantly different ( P <0.05) and significantly correlated with EGFR mutation ( P <0.05). Follow-up showed that the patients with disease free survival, recurrence and metastasis and death were the most in type I, type II and type I, respectively. Conclusions: In this study, the distribution of tumor immunomicroenvironmental typing in NSCLC patients was mainly the highest in type I and the lowest in type Ⅲ, which was related to EGFR mutation, smoking history and pathological differentiation. Patients with EGFR mutations were mainly of type Ⅱand type Ⅳ, and were associated with low expression of PD-L1. ··

Progress on Anticancer Effects of PD-1/PD-L1 Checkpoint Inhibitors / 中国药学杂志

This artical explained the biological action mechanism of PD-1/PD-L1 monoclonal antibodies through reactivating the immune response of T cells to tumor cells immune response, analyzed the detection reports on the targets, introduced the clinical manifestations and indications research results, and looked into their development potential in the field of anticancer therapy. It's important to rationally use PD-1/PD-L1 monoclonal antibodies to decrease immune-mediated adverse events as well as maximizing the therapeutic effect. Furthermore, we should not only see the accomplishment in anticancer therapy, but also gain insight into its development direction in the field of anticancer research based on the therapeutic idea of inducing autoimmune system to kill tumor cells.

Role of PD-1/PD-L1 in microenvironment of breast cancer / 中华肿瘤杂志

Programmed cell death protein 1 (PD-1), as a checkpoint of the immune signaling pathway, is a hotspot in the field of immuno-oncology. Its binding with ligand (PD-L1) is an important negative regulatory mechanism. Application of PD-1/PD-L1 inhibitors in treatments of breast cancer is still being explored at present. Fully understanding the mechanism of PD-1/PD-L1 in the microenvironment of breast cancer will help their inhibitors play a full role. This review will start with the discovery of PD-1 and PD-L1, describe their main signaling pathways, introduce the common types and applications of PD-1/PD-L1 inhibitors, especially in breast cancer, summarize the basic research of PD-1 and PD-L1 in breast cancer microenvironment in recent years, and seek new strategies of PD-1/PD-L1 inhibitors in breast cancer treatment.

Correlation between Ki-67 and PD-L1 expression in non-small cell lung cancer tissues and its effect on patients’prognosis / 中国肿瘤生物治疗杂志

@# Objective:To investigate the relationship between Ki-67 and PD-L1 in patients with non-small cell lung cancer (NSCLC) and their effects on prognosis. Methods: A total of 401patients, who were pathologically diagnosed as NSCLC in Changhai Hospital from January 2012 toAugust 2018, were enrolled as study subjects; and the patients were immunohistochemically tested for PD-L1 and Ki-67. The clinical and pathological data were collected, and the follow-up was performed regularly. The correlation between Ki-67 and PD-L1 and their effects on postoperative DFS and post-chemotherapy PFS were statistically analyzed. Results: Positive rates of PD-L1 and Ki-67 in NSCLC tissues were 37.9% (152/401) and 96.3% (386/401), respectively. Univariate analysis showed that Ki-67 was an influencing factor for PD-L1 expression (OR=0.33, 95%CI=0.28-0.39, P<0.0001); Curve Fitting analysis showed a positive correlation between Ki-67 and PD-L1; threshold effect analysis, segmentation multivariate logistic and ROC curve analysis showed 14% is a relatively suitable threshold for Ki-67 to be combined with PD-L1. Kaplan-Meier analysis showed that patients in Ki-67 high expression group had a significantly shorter post-operative DFS than those in Ki-67 low expression group ([21.88±11.25] vs [41.22±16.25]m, P< 0.0001), patients in PD-L1 positive group had a significantly shorter DFS than those in PD-L1 negative group ([24.75±14.59] vs [38.27± 16.75]m, P<0.0001)], and patients in Ki-67 high/PD-L1 positive group had the shortest DFS as compared to the other three groups ([20.57±11.33] vs [24.11±10.79], [36.00±16.79], [42.91±15.77]m, P<0.0001).As for post-chemotherapy PFS, patients in Ki-67 high expression group was significantly longer than those in Ki-67 low expression group [(7.70±3.01) vs (5.80±2.99)m, P=0.016), but there was no significant difference between PD-L1 positive group and PD-L1 negative group [(7.04±3.21) vs (6.33±3.06)m, P=0.22); for combined evaluation with Ki-67 and PD-L1, the PFS of two Ki-67 high expression groups was significantly longer than the other two Ki-67 low expression groups [(7.74±3.25) vs (7.43±2.38) vs (4.91±1.97) vs (6.02±3.19)m, P=0.041). Conclusion: Ki-67 is positively correlated with PD-L1 in NSCLC patients, and Ki-67 14% is a suitable threshold for combined use with PD-L1. Both Ki-67 and PD-L1 are predictors of poor prognosis. The combination of the two has an "additive effect" on the prediction of poor prognosis, and patients with high Ki-67 expression are more sensitive to chemotherapy.

Expression of PD-L1 in triple negative breast cancer tissues and its relationship with angiogenesis / 中国肿瘤生物治疗杂志

@# Objective: To investigate the expressions of programmed death ligand 1（PD-L1）in triple-negative breast cancer (TNBC) and its correlation with angiogenesis. Methods: 120 cases of TNBC patients who underwent surgery in the Fourth Hospital of Hebei Medical University from March 1, 2011 to June 1, 2012 were collected. The tumor tissues of patients were surgically resected and confirmed by pathology. PD-L1 protein expression in TNBC tissues of 120 patients was detected by tissue microarray combined with immunohistochemistry, and its relationship with various clinical indicators was analyzed. Blood vessels and lymphatic vessels were labeled withCD34andD2-40todetectmicrovesseldensity(MVD)andlymphaticvesseldensity(LVD)inTNBC.Results:Thepositiveexpression rate of PD-L1 in the tumor cells and interstitial infiltrating lymphocytes fromTNBC was 56.7% (68/120); No correlation was found between PD-L1 protein expression and the gender, age, histological grade, clinical stage, or tumor size of patients with TNBC (P>0.05), but related to the lymph node metastasis (P<0.05) and vascular thrombus (P<0.05). TNBC with high PD-L1 expression exhibited high incidence of lymph node metastasis and formation of vascular thrombus, and the expression of PD-L1 was positively correlated with MVD (r=0.500, P=0.02) as well as LVD (r=0.662, P=0.01). Log-Rank test showed that the survival time of TNBC patients with positive PD-L1 protein expression was significantly shorter than that of patients with negative expression (P<0.05). Cox multivariate analysis suggested that PD-L1 protein expression could be an independent prognostic factor for TNBC overall survival. Conclusion: PD-L1 plays an important role in TNBC angiogenesis and lymphangiogenesis, and is closely related to TNBC invasion and metastasis; blocking PD1/PD-L1 signal pathway is expected to be an effective new strategy for TNBC treatment.

Change of peripheral blood sPD-L1 during chemotherapy in patients with small cell lung cancer and its clinical significance / 中国肿瘤临床

Objective: In tumor microenvironment, immune-related mechanisms up-regulate the expression of programmed death li-gand 1 (PD-L1), which abnormally activates PD-L1 signaling pathway and mediates tumor immune escape. Soluble programmed death ligand 1 (sPD-L1) is a form of PD-L1. It has been confirmed that the expression of sPD-L1 in lung squamous cell carcinoma and adeno-carcinoma is related to disease progression, while small cell lung cancer (SCLC) has a high degree of malignancy, strong invasiveness and few related studies. The purpose of this study was to observe the changes in expression of sPD-L1 in the plasma of SCLC patients and their clinical significance. Methods: A total of 94 patients with SCLC diagnosed by pathological examination in Shanxi Provincial Cancer Hospital from March 2018 to November 2018 were selected as test group, and 17 healthy persons in the same period were se-lected as control group. The dynamic changes of plasma sPD-L1 were compared between the two groups, and the correlations among the expression of sPD-L1 and TNM stage, distant metastasis, and pro-gastrin-releasing peptide (ProGRP) was analyzed. Results: The lev-el of sPD-L1 in the test group was higher than that in the control group (P<0.05 and P<0.01, respectively). In patients with SCLC in the remission stage, the serum sPD-L1 level after chemotherapy was significantly lower than that before chemotherapy (P<0.01); in pa-tients with advanced stage, the serum sPD-L1 level after chemotherapy was significantly higher than that before chemotherapy (P<0.01). The abnormal high expression of sPD-L1 in SCLC patients was significantly correlated with the progression of the disease (P<0.05). The expression of sPD-L1 in serum was positively correlated with the tumor marker ProGRP. Conclusions: The expression of sPD-L1 in peripheral plasma of patients with SCLC is higher than that in healthy individuals and is closely related to the clinical effect.

Relationship between PD-L1 protein expression and gene amplification in gastric cancer tissues / 中华病理学杂志

Objective@#To investigate the relationship of PD-L1 protein expression and gene amplification in gastric cancer and their correlation with clinicopathologic factors.@*Methods@#The cohort included 247 gastric cancer specimens with follow-up data and clinicopathologic data obtained from Shanxi Cancer Hospital in 2011. PD-L1 expression was detected by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH).@*Results@#PD-L1 protein was expressed in 25.9% (64/247) of the tumor cells and 26.7% (66/247) of the tumor infiltrating immune cells (IC). There was a correlation between the two (P<0.01). The expression of PD-L1 in tumor cells correlated with the degree of differentiation and tumor diameter(P<0.05). The PD-L1 expression in IC correlated with vascular tumor thrombi(P<0.05). The amplification rate of PD-L1 gene detected by FISH was 19.0% (47/247), and was associated with age, large/small curvature of the stomach, tumor location, tumor diameter, and lymph node metastasis(P<0.05). The positive coincidence rate of the two methods was 25.0% (16/64), negative coincidence rate was 83.0% (152/183), and total coincidence rate was 68.0% (168/247), suggesting that the coincidence of IHC and FISH was poor (P=0.157). There was a negative correlation between PD-L1 protein expression on tumor cells and prognosis in gastric cancer. There was no significant correlation between PD-L1 protein expression on IC and PD-L1 gene amplification with prognosis. Vascular tumor thrombi, tumor diameter, depth of invasion, and lymph node metastasis were all poor prognostic factors of gastric cancer(P<0.05). Multivariate Cox regression analysis showed that PD-L1 protein expression, depth of invasion and lymph node metastasis were all independent prognostic risk factors for gastric cancer.@*Conclusions@#Concordance between PD-L1 protein expression and gene amplification is poor. PD-L1 protein expression may signify poor prognosis. There is no significant correlation between PD-L1 gene amplification and prognosis of patients with gastric cancer.

Bridging intergrator-1 inhibits the expression of PD-L1 through c-MYC pathway in non-small cell lung cancerA549 cells / 中国肿瘤生物治疗杂志

@# Objective: To investigate the effect and mechanism of bridging intergrator-1 (BIN1) on expression of programmed death-ligand 1 (PD-L1) in non-small cell lung cancer (NSCLC) A549 cells. Methods: Quantitative real-time polymerase chain reaction (qRTPCR) and Western blotting were used to detect the mRNA and protein expression of BIN1 and PD-L1 in A549 cells and normal human embryo lung fibroblast 2BS cells, respectively. Eukaryotic expression plasmid CMV-MCS-GFP-SV40-Neomycin-BIN1 containing human full length BIN1 gene sequence was transfected into A549 cells via cationic liposomes by using gene transfection technology (as BIN1+group); c-MYC-siRNAwas used to knockdown the expression of c-MYC inA549 cells through RNAinterference technique (as cMYC-siRNA group). The transfection efficiencies were verified by qRT-PCR and Western blotting, the effects of BIN1 over-expression and c-MYC knock-down on the expression of c-MYC and PD-L1 in A549 cells were detected as well. Results: Comparing with 2BS cells, the expression of BIN1 was down-regulated in A549 cells at both mRNA and protein levels, while the expression of PD-L1 was up-regulated (all P<0.05). The expression of BIN1 was increased at both mRNA and protein level in BIN1+ group, while the expression of PD-L1 was decreased significantly after B1N1 transfection (all P<0.05). After transfection of c-MYC-siRNA into A549 cells, the expression of c-MYC and PD-L1 in c-MYC-siRNAgroup was down-regulated significantly (all P<0.01). Conclusion: Over-expression of BIN1 could reduce the expression of PD-L1 by inactivating the c-MYC pathway, thereby inhibiting the immune escape ofA549 cells.

Expression and clinical significance of PD-1/PD-Ls in EBV-positive T/NK lymphoprolif-erative disorders / 中国肿瘤临床

Objective: To investigate the expression and clinical significance of programmed death-ligand 1 (PD-L1), programmed death-ligand 2 (PD-L2), and their receptor programmed cell death protein 1 (PD-1) in EBV-positive T/NK lymphoproliferative disease [Epstein-Barr virus-positive T/natural killer (NK)-cell lymphoproliferative disease, EBV(+)-T/NK-LPD]. Methods: The pathological paraffin-embedded tissues of 17 patients with EBV(+)-T/NK-LPD from the First Affiliated Hospital of Zhengzhou University from January 2013 to December 2017 were collected. These patients include 12 males and 5 females, aged 10-82 years old, the average age being 29 years, 4 people in gradeⅠ, 7 in gradeⅡ, 3 in gradeⅢ, and 3 people with hydroa vacciniforme-like lymphoproliferative disorders. Immunohistochemical SP method was used to detect the expression of PD-1, PD-L1, and PD-L2 in human EBV(+)-T/NK-LPD tissues. The relationship between PD-1, PD-L1, PD-L2 expression, and clinicopathological parameters, pathological grades and prognosis were analyzed by Fisher's exact probabilities and Spearman rank correlation. Result: After statistical analysis, the results showed that in 17 cases of tissue samples, there were 12 cases with positive PD-1 expression, 6 cases with positive PD-L1 expression and 5 cases with positive PD-L2 expression. There was no significant correlation between PD-1 and PD-L2 expression and prognosis (P>0.05). PD-L1 expression showed a positive correlation with prognosis (P<0.05). There was no significant correlation between the expression of PD-L1 and PD-L2 with age, sex, as well as LDH and Ki-67 levels (P>0.05). Moreover, there was no significant correlation of PD-1 and PD-L2 expression with pathological grade (r=0.141, r=-0.149, both P>0.05). However, there was a negative correlation between the PD-L1 expression and pathological grade (r=-0.563), and the correlation between the PD-L1 ex-pression and pathological grade was statistically significant (P<0.05). Conclusions: PD-1, PD-L1, and PD-L2 are abnormally expressed in the pathological tissues of EBV(+)-T/NK-LPD. Although there was no significant correlation between the expression of PD-1 and prognosis or pathological grade, it was significantly higher in EBV+T/NK-LPD. PD-1/PD-Ls associated signaling pathway is expected to be a potential new target for EBV(+)-T/NK-LPD immunotherapy.

Application of programmed cell death protein 1/programmed death-ligand 1 blockade in advanced gastric cancer treatment / 上海交通大学学报（医学版）

In the tumor microenvironment, the interaction of programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) can promote the immune escape of tumor cells. The application of PD-1/PD-L1 blockade can restore host immune function to efficiently identify and kill tumor cells. In recent years, PD-1/PD-L1 blockade has shown remarkable clinical effects in a variety of tumors and U.S. Food and Drug Administration has approved nivolumab and pembrolizumab for the treatment of unresectable/metastatic melanoma, non-small cell lung cancer and etc. Hence, a growing number of clinical trials on PD-1/PD-L1 blockade for advanced gastric cancer have been carried out, and the overall survival and objective response rate of most trials are promising. This paper reviewed PD-1/PD-L1 signaling pathway, the relationship between the expression of PD-L1 and the classification and prognosis of gastric cancer, and the clinical results of PD-1/PD-L1 blockade in advanced gastric cancer.

The expression and significance of PD-1 and PD-L1 in peripheral blood mononuclear cells of OLP patients / 实用口腔医学杂志

Objective:To explore the expression of PD-1 mRNA and PD-L1 mRNA in peripheral blood mononuclear cells(PBMCs)of OLP patients.Methods:The peripheral blood lymphocyte subsets (CD3 +,CD4 +,CD8 +,CD1 9 +,CD1 6 ++56 +)and humoral immunity indexes (lgG,lgA,lgM,C3,C4)were detected in 36 patients with OLP by flow cytometry and nephelometry respectively.The expres-sions of PD-1 mRNA and PD-L1 mRNA in PBMCs of 36 patients with OLP and 1 8 healthy individuals(the controls)were detected by fluorescence quantitative PCR,the correlation of PD-1 mRNA or PD-L1 mRNA with the immune function of OLP patients was analysed. Results:In OLP patients the percentages of peripheral blood lymphocyte subsets (CD3 +,CD4 +,CD8 +,CD1 9 +,CD1 6 + +56 +)as well as the complement of C3 and C4 were lower(P <0.05),the percentages of CD1 9 +(B)and the level of lgMwere higher(P <0.05),the expression levels of PD-1 mRNA and PD-L1 mRNA in rPBMCs were higher(P <0.05)than in the controls.There was positive correla-tion between PD-1 mRNA and PD-L1 mRNA expression level.The expression level of PD-1 mRNA was negatively correlated with CD4 +,but positively with lgG,the expression level of PD-L1 mRNA was positively correlated with CD1 9 +.Conclusion:The up-regu-lation of PD-1 mRNA and PD-L1 mRNA in PBMCs is correlated with the immunity of OLP patients.PD-1 /PD-L1 pathway may play an important role in immune pathogenesis of OLP.

Association Between PD-L1 and HPV Status and the Prognostic Value of PD-L1 in Oropharyngeal Squamous Cell Carcinoma / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Oropharyngeal squamous cell carcinoma (OSCC) has been recognized as an immunosuppressive disease. Various mechanisms have been proposed for immune escape, including dysregulation of immune checkpoints such as the PD-1:PD-L1 pathway. We investigated the expression of programmed cell death-ligand 1 (PD-L1) in HPV-negative and HPV-positive OSCC to determine its prevalence and prognostic relevance. MATERIALS AND METHODS: Using immunohistochemistry, 133 cases of OSCC were evaluated for expression of PD-L1. Formalin-fixed paraffin-embedded tumor samples were stained with monoclonal antibody (clone 5H1) to PD-L1. PD-L1 positivity was defined as membrane staining in ≥20% of tumor cells. Correlations between PD-L1 expression and HPV status and survival parameters were analyzed. RESULTS: Of the 133 patients, 68% showed PD-L1 expression, and 67% of patients were positive for p16 expression by immunohistochemistry. No significant difference in PD-L1 expression was observed between HPV(-) and HPV(+) tumors (61% vs. 71%, p=0.274). No significant difference in age, gender, smoking history, location of tumor origin, or stage was observed according to PD-L1 status. With a median follow-up period of 44 months, older age (≥65) (p=0.017) and T3-4 stage (p<0.001) were associated with poor overall survival (OS), whereas PD-L1 expression did not affect OS in univariate and multivariate analysis. CONCLUSION: PD-L1 expression was observed in the majority of OSCC patients regardless of HPV status. Further large prospective studies are required to determine the role of PD-L1 expression as a prognostic or predictive biomarker, and clinical studies of immune checkpoint inhibitors in OCSS are warranted regardless of HPV status.