Clinical Significance Of PD-L1 Research Articles

Prognostic and Clinical Significance of PD-L1, EGFR and Androgen Receptor (AR) Expression in Triple-Negative Breast Cancer (TNBC) Patients.

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype and is associated with high recurrence rates, a high incidence of distant metastases and poor overall survival. The aim of this study was to investigate the role of PD-L1, EGFR and AR expression in TNBC promotion and progression. To that end, we analyzed the immunohistochemical expression of these genes in 125 TNBC patients and their relation to clinicopathological parameters and survival. An elevated expression of PD-L1 was significantly correlated with higher tumor and nuclear grade, while a low expression was correlated with loco-regional recurrence without any influence on survival. Contrary to this, the expression of AR showed a positive impact on the DFI and a negative association with tumor grade. Furthermore, PD-L1 and AR demonstrated simultaneous expression, and further co-expression analysis revealed that a positive expression of PD-L1/AR notably correlates with tumor and nuclear grade and has a significant impact on a longer DFI and OS, while a negative PD-L1/AR expression is significantly associated with metastases. Therefore, our results suggest that positive PD-L1/AR expression is beneficial for TNBC patients. In addition, an elevated expression of EGFR contributes to metastases and a worse DFI and OS. In conclusion, we think that low PD-L1/low AR/high EGFR expression followed by high Ki67 expression constitutes a 'high risk' profile of TNBC.

Expression comparison and clinical significance of PD-L1 (22C3) and PD-L1 (SP142) in triple negative breast cancer

Objective: To investigate the expression of programmed death ligand-1 (PD-L1, SP142) and PD-L1 (22C3) in triple-negative breast cancer (TNBC), and analyze their correlation with the clinicopathological factors and prognosis. Methods: The clinicopathologic data of 259 patients with TNBC treated in Cancer Hospital from August 2010 to December 2013 were collected. Whole section of surgical tissue samples were collected to conduct PD-L1 (SP142) and PD-L1 (22C3) immunohistochemical (IHC) staining. The PD-L1 expression in tumor cells and tumor infiltrating immune cells were visually assessed respectively, the relationship between PD-L1 expression and clinicopathologic characterizes were analyzed. Univariable and multivariable Cox proportional hazards regression models were used to test the correlations between PD-L1 expression and disease-free survival (DFS) and overall survival (OS). Results: The positive rates of SP142 (immune cell score, ICs≥1%) and 22C3 (combined positive score, CPS≥1) were 42.1%(109/259) and 41.3%(107/259) in TNBC tissues, respectively, with a total coincidence rate of 82.3%. The Kappa value of positive expression cases was 0.571 and the distribution difference of SP142 and 22C3 positive expression cases was statistically significant (P<0.001). The PD-L1 positive patients were less likely to have vascular invasion (P<0.05), but with higher histological grade and Ki-67 proliferation index (P<0.05). The recurrence/metastasis cases(8) of the patients with positive PD-L1 (SP142) was significantly lower than that of patients with negative PD-L1(SP142, 27, P=0.016). The positive expression of PD-L1 (SP142) patients were longer DFS (P=0.019). The OS of patients with positive PD-L1 (SP142) were longer than those with negative PD-L1 (SP142), but without significance (P=0.116). The positive expression of PD-L1 (22C3) was marginally associated with DFS and OS of patients (P>0.05). Conclusions: The expression of PD-L1 (22C3) is different from that of PD-L1 (SP142) in TNBC, and the two antibodies can't be interchangeable for each other in clinical tests. PD-L1 (SP142) status is an independent prognostic factor of DFS in TNBC. The DFS is significantly prolonged in patients with positive expression of PD-L1 (SP142).

1176P Expression and clinical significance of PD-L1 in small cell carcinoma of the esophagus

1176P Expression and clinical significance of PD-L1 in small cell carcinoma of the esophagus

Abstract 5381: Elevated PD-L1 and HER2 expression on aneuploid carcinoma cells in malignant ascites accelerate stumor cell immune evasion in gastrointestinal cancer patients

Abstract Background Peritoneal dissemination (PD) is a type of metastasis frequently found in gastrointestinal (GI) cancer patients, resulting in the production of massive malignant ascites which associate with poor prognosis. However, the question of how the expression of tumor biomarkers on cancer cells in malignant ascites correlates with PD is yet to be answered. This study aims to investigate the clinical significance of PD-L1 and HER2 expression on malignant ascites disseminated tumor cells (maDTCs) in GI carcinoma patients. Patients and Methods Paired blood and malignant ascites specimens were respectively collected from 24 of metastatic GI subjects, including 15 gastric, 2 pancreatic, 1 esophageal, and 6 colorectal cancer patients. Non-hematologic CTCs and maDTCs were enriched by subtraction enrichment (SE), followed by immunostaining-FISH (iFISH) to co-examine PD-L1 and HER2 expression on aneuploid maDTCs and CTCs. In addition, CD4+, CD8+, Treg and naive T cells in the same cohort of samples were quantified by flow cytometry. Results In situ karyotypic and phenotypic characterization performed by iFISH showed that the average number of maDTCs in the 24 patients was 32755/ml ascites, which was significantly higher than the average number of CTCs detected (3.5/ml blood) (P&amp;lt;0.0001). The number of maDTCs and CTCs exhibited no correlation between each other (Pearson's product-moment correlation coefficient, R=-0.03, P=0.89). Further examination indicated that PD-L1 was expressed on 50% of maDTCs compared to only 11% for CTCs (P=0.0002). No correlation of PD-L1 expression between maDTCs and CTCs was observed (Pearson's product-moment correlation coefficient, R=0.25, P=0.24). Co-expression of PD-L1 and HER2 on CTCs and maDTCs was respectively examined in the recruited 15 gastric cancer (GA) patients. All 15 patients were histopathological HER2 negative (hHER2-). One subject (1/15=6.7%) showed 1 double HER2+/PD-L1+ CTC (1/63 CTCs in 15 GA patients=1.6%). In comparison, 6 patients (6/15=40%) had a total of 290377 HER2+/PD-L1+ maDTCs detected (290377/1306783 overall maDTCs=22%). In addition, flow cytometry analyses revealed that 5% of lymphocytes in malignant ascites were immunosuppression relevant regulatory T cells (Tregs), compared to only 2% of Tregs identified in the paired peripheral blood sample of the same patient. Conclusions Our study suggested that a higher proportion of Tregs in malignant ascites may contribute towards fostering an immunosuppressive microenvironment.PD-L1+/HER2+ maDTCs, in such an immunosuppressive microenvironment, might be able to evade immune system attack. Moreover, PD-L1 and HER2 identified on maDTCs could serve as therapy targets with respect to inhibition of peritoneal metastasis, potentially leading to an additional treatment strategy for GI cancer patients with malignant ascites. Citation Format: Yang Chen, Changsong Qi, JiaJia Yuan, Dan Liu, Zhi Peng, Xiaotian Zhang, Jian Li, Pin Peter Lin, Yilin Li, Lin Shen. Elevated PD-L1 and HER2 expression on aneuploid carcinoma cells in malignant ascites accelerate stumor cell immune evasion in gastrointestinal cancer patients [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5381.

PD-L1 Overexpression on Tumor-Infiltrating Lymphocytes Related to Better Prognosis of Colorectal Cancer.

PD-L1 expression on tumor-infiltrating lymphocytes (TILs) has recently been reported as a biomarker for colorectal cancer (CRC). However, the prognostic and clinical significance of PD-L1 on TILs in CRC remains controversial. We performed this meta-analysis to evaluate the association between the PD-L1 expression on TILs and clinicopathological features and prognosis of CRC patients. A comprehensive literature search for relevant studies published up to Feb 2020 was performed using Medline, Embase, and Web of Science. Odds ratio (OR) with 95% CI was selected to appraise the correlation between PD-L1 expression on TILs with prognostic and clinicopathological characteristics of CRC patients. Begg's and Egger's test were used to assess publication bias. The statistical analysis was conducted using Stata software. A total of 19 studies including 5,213 CRC cases were included in this meta-analysis. The pooled results showed that PD-L1 overexpression on TILs was relevant to longer OS (OR = 1.36, 95% CI = 1.19 - 1.55, p < 0.01) and longer DFS/RFS (OR = 1.22, 95% CI = 1.03 - 1.44, p = 0.02). Moreover, CRC patients with high expression of PD-L1 on TILS was associated with lower T stage (OR = 2.30, 95% CI = 1.85 - 2.87, p < 0.01), less lymph node in-vasion (OR = 1.48, 95% CI = 1.03 - 2.13, p = 0.03), less distant metastasis (OR = 2.56, 95% CI = 1.81 - 3.64, p < 0.01), earlier TNM stage (OR = 1.93, 95% CI = 1.34 - 2.66, p < 0.01), later tumor grade (OR = 0.38, 95% CI = 0.23 - 0.62, p < 0.01) and high MSI status (OR = 0.36, 95% CI = 0.25 - 0.52, p < 0.01). But it is not related to tumor size, tumor differentiation, MMR status, BRAF mutant, and KRAS mutant. This meta-analysis revealed that PD-L1 expression on TILs can serve as a significant biomarker for positive prognosis and clinicopathological features of CRC. Our results may provide some useful information when using PD-L1 expression to predict the survival of CRC patients and to select the beneficial CRC patients from PD-1/PD-L1 antibody treatment.

PD-L1 regulates tumorigenesis and autophagy of ovarian cancer by activating mTORC signaling.

PD-L1 is a well-known immune co-stimulatory molecule that regulates tumour cell escape from immunity by suppressing the immune response. However, the clinical significance of PD-L1 in the progression of ovarian cancer is unclear. Our study demonstrated that PD-L1 is up-regulated in ovarian tumour tissue compared with its expression level in adjacent normal tissue. Furthermore, we confirmed that PD-L1 increases the proliferation of cancer cells by activating the AKT-mTORC signalling pathway, which is also enhanced by the expression of S6K, the substrate of mTORC. In addition, PD-L1 promotes the autophagy of ovarian cancer cells by up-regulating the expression of BECN1, a crucial molecule involved in the regulation of autophagy. In conclusion, PD-L1 may provide a target for the development of a novel strategy for the treatment of ovarian cancer.

Expression and clinical significance of PD-L1 and c-Myc in non-small cell lung cancer.

It is known that there are insufficient prognostic factors for non-small cell lung cancer (NSCLC). It was reported that PD-L1 was a prognostic factor for NSCLC,and c-Myc regulated the expression of PD-L1. Herein, we investigated c-Myc and PD-L1 expression and their association with overall survival (OS) in NSCLC. Formalin-fixed paraffin-embedded specimens were obtained from 128 patients with surgically resected primary NSCLC. Immunohistochemistry was used to assess the expression of PD-L1 and c-Myc in this study. Pearson's Chi squared test or Fisher's exact test was used to analyze the correlation of the expression of PD-L1 and c-Myc with clinicopathologic features. The relationship between OS and the expression of PD-L1 and c-Myc was evaluated by the Kaplan-Meier method and Cox proportional hazards model, respectively. Positive expression of PD-L1 was detected in 59 patients (46.1%). Patients with negative expression of PD-L1 had remarkably longer OS than those with positive expression of PD-L1. The positive expression rate of c-Myc in NSCLC accounted for 58.6% (75/128) and its expression was significantly more frequent in males (p = 0.002) and patients with lymph node metastasis (p = 0.029). PD-L1 expression was positively correlated with c-Myc expression (r = 0.459, p < 0.001). The PD-L1 and c-Myc double-positive group had a worse prognosis than other subgroups (p < 0.05), and the PD-L1 and c-Myc double-negative group had a better OS than other subgroups (p < 0.05). Conjoint analysis of the expression of PD-L1 and c-Myc was a better prognostic approach for NSCLC patients.

PD-L1 expression on tumor-infiltrating immune cells is highly associated with M2 TAM and aggressive malignant potential in patients with resected non-small cell lung cancer

ObjectivesPD-L1 expression on tumor cells (TCs) and tumor-infiltrating immune cells (ICs) plays important roles in regulating the antitumor T cell response. However, the mechanistic and clinical significance of the effect of PD-L1 on TCs versus ICs remains unclear. On the other hand, tumor-associated macrophages (TAMs), M2 macrophages in particular, can promote tumor progression. MethodsWe evaluated PD-L1 expression on TCs and ICs using Ventana SP263 assay and the stromal M2 TAM distribution using CD163 staining in 160 consecutive patients with resected non-small cell lung cancer (NSCLC). ResultsPD-L1 expression on TCs and ICs was significantly higher in stromal M2 TAM-high group than in stromal M2 TAM-low group (p < 0.001 and p < 0.001, respectively). Regarding the clinical significance of PD-L1, PD-L1 expression on TCs was significantly associated with histology (p = 0.001), tumor differentiation (p < 0.001) and nodal status (p = 0.029). Furthermore, PD-L1 expression on ICs was significantly associated with histology (p < 0.001), tumor differentiation (p < 0.001), tumor status (p = 0.024), nodal status (p = 0.016), and pathologic stage (p = 0.004). The disease-free survival rate was significantly lower in patients with PD-L1-positive TC than in those with PD-L1-negative TC (p = 0.023), as well as in patients with PD-L1-positive IC than in those with PD-L1-negative IC (p < 0.001). Furthermore, the overall survival rate was significantly lower in patients with PD-L1-positive IC than in those with PD-L1-negative IC (p = 0.023). ConclusionsDuring tumor progression in NSCLC, the presence of M2 TAMs might affect PD-L1 expression both on TCs and ICs. In patients with NSCLC, PD-L1 expression both on TCs and ICs was associated with malignant behaviors, which was more in case of ICs.

Expression and Clinical Significance of PD-L1 and MicroRNA-138-5p in Patients with Acute Myeloid Leukemia

To investigate the expression and clinical significance of PD-L1 and microRNA-138-5p in the peripheral blood mononuclear cells of patients with acute myeloid leukemia. The SYBR GreenⅠreal-time PCR was used to detect the expression levels of PD-L1 mRNA and miR-138 in 20 cases of primary AML, 9 cases of relapsed/refractory AML and 8 cases of complete remission. The samples of peripheral blood of 20 healthy peoples were used as controls. The expression levels of PD-L1 in both the primary AML and the relapsed/refractory AML groups were significantly higher than those in the healthy control group (P<0.01), and the expression level of PD-L1 in the relapsed/refractory AML group was significantly higher than that in the primary AML group (P<0.01). The expression level of miR-138 in both the primary AML and the relapsed/refractory AML groups were significantly lower than that in the healthy control group (P<0.01). The 8 sampes out of 20 cases of primary AML patients achieved complete remission (CR) were collected and detected. The results showed that the expression level of miR-138 in the complete remission group was higher than that in the primary AML group (P<0.05), but the expression level of PD-L1 mRNA in the CR group was not significantly different from that in the primary AML group (P>0.05). and there was a negative correlation between PD-L1 mRNA and miR-138 in primary AML patients (P<0.05). The expression of PD-L1 increases and the expression of miR-138 down-regulates in PBMNCs of AML patients, furthermore, both correlate each other.

Expression and clinical significance of PD-L1, B7-H3, B7-H4 and TILs in human small cell lung Cancer (SCLC)

BackgroundSmall cell lung cancer (SCLC) accounts for 10–15% of all lung malignancies and its prognosis is dismal. Although early studies have shown promising clinical activity of immune checkpoint blockers, the immune composition and expression of potentially actionable immunostimulatory targets in this malignancy are poorly understood.MethodsUsing multiplexed quantitative immunofluorescence (QIF), we measured the levels of 3 different B7 family ligands PD-L1, B7-H3, B7-H4 and major tumor infiltrating lymphocyte (TIL) subsets in 90 SCLC samples represented in tissue microarray format. Associations between the marker levels, clinicopathological variables and survival were studied.ResultsPD-L1 protein was detected in 7.3%, B7-H3 in 64.9% and B7-H4 in 2.6% of SCLC cases. The markers showed limited co-expression and were not associated with the level of TILs, age, gender and stage. Elevated B7-H4 was associated with shorter 5-year overall survival. The levels of CD3+, CD8+ and CD20+ TILs and the ratio of total/effector T-cells were significantly lower in SCLC than in non-small cell lung cancer. High levels of CD3+, but not CD8+ or CD20+ TILs were significantly associated with longer survival.ConclusionsTaken together, our study indicate variable expression and clinical role of B7-family ligands in SCLC with predominant expression of the candidate target B7-H3 and the presence of a limited cytotoxic anti-tumor immune response. These results support the evaluation of B7-H3 blockers and/or pro-inflammatory therapies in SCLC.

PD-L1和PD-1在前列腺癌中的表达及其临床意义

PD-L1和PD-1在前列腺癌中的表达及其临床意义

The clinical significance of PD-L1 in advanced gastric cancer is dependent on ARID1A mutations and ATM expression

ABSTRACTWhether PD-L1 expression is associated with survival outcomes in gastric cancer (GC) is controversial. The inhibition of the PD-1/PD-L1 pathway is effective against genomically unstable tumors. Hypothesizing that also the clinical significance of PD-L1 might be dependent on the activation of molecular circuits ensuring genomic stability, we evaluated PD-L1 expression in tissue samples from 72 advanced GC patients treated with first-line chemotherapy. Samples were already characterized for DNA damage repair (DDR) component expression (pATM, pChk1, pWee1, γ-H2AX and pRPA2) along with mutations in DDR-linked genes (TP53 and ARID1A). Overall, PD-L1 expression was not associated with progression-free survival (PFS) and overall survival (OS), independently on whether we considered its expression in tumor cells (PD-L1-TCs) or in the immune infiltrate (PD-L1-TILs). In subgroup analysis, positive PD-L1-TC immunostaining was associated with better PFS in patients whose tumors did not carry DDR activation (multivariate Cox: HR 0.34, 95%CI: 0.15–0.76, p = 0.008). This subset (DDRoff) was characterized by negative pATM expression or the presence of ARID1A mutations. Conversely, the relationship between PD-L1-TC expression and PFS was lost in a molecular scenario denoting DDR activation (DDRon), as defined by concomitant pATM expression and ARID1A wild-type form. Surprisingly, while PD-L1-TC expression was associated with better OS in the DDRoff subset (multivariate Cox: HR 0.41, 95% CI: 0.17–0.96, p = 0.039), in the DDRon subgroup we observed an opposite impact on OS (multivariate Cox: HR 2.56, 95%CI: 1.06–6.16, p = 0.036). Thus, PD-L1-TC expression may impact survival outcomes in GC on the basis of the activation/inactivation of genome-safeguarding pathways.

Clinical Significance of PD-L1+ Exosomes in Plasma of Head and Neck Cancer Patients.

Circulating PD-L1high exosomes in HNC patients' plasma but not soluble PD-L1 levels associate with disease progression. Clin Cancer Res; 24(4); 896-905. ©2017 AACR.

Expression and Significance of PD-L1, HSP90 and HSP90α in Serum of Patients with Acute Leukemia

To explore the expression and clinical significance of PD-L1, heat shock protein 90 (HSP90) and HSP90α in the serum of patients with acute leukemia (AL) of different types and disease stages. A total of 84 AL patients from January 2013 to October 2016 in our hospital and 20 healthy persons as controls were selected. All the samples of serum or bone marrow were separated. The protein expression levels of serum HSP90, HSP90α were detected by ELISA. The flow cytometry was used to detect PD-L1 expression. The relationship of the expression level of PD-L1, HSP 90, and HSP90α with clinical outcome was analyzed. The expression levels of serum HSP90, HSP90α and PD-L1 positive rate in AL patients were significantly higher those that in control group (P<0.05), the expression levels of serum HSP90, HSP90α and PD-L1 positive rate of Al patients in remission were lower than those in newly diagnosed patients (P<0.05). The expression level of HSP90, HSP90α and PD-L1 positive rate in the relapsed AL patients were higher than those in newly diagnosed AL patients and patients in remission (P<0.05). There was no significant difference of HSP90 protein level and PD-L1 positive rate between newly diagnosed AML patients and ALL patients(P>0.05). HSP90α level of newly diagnosed AML patients was lower than that in newly diagnosed ALL (P<0.05). HSP90α and HSP90 levels and PD-L1 positive rate in no remission patients were significantly higher than those in complete remission patients (P<0.05). The HSP90α level in patients without recurrence decreased during chemotherapy. The HSP90α protein level was the lowest after the hematopoietic stem cell transplantation, but increased after relapse. The PD-L1,HSP90 and HSP90α play an important role in the developmental process of acute leukemia, which can be used as reference indications to assess clinical efficacy and prognosis.

Abstract 3989: Different expression and prognostic effect of PD-L1/PD-1 in SCC and non-SCC of non-small cell lung cancer

Abstract Although checkpoint inhibitors targeting PD-1/PD-L1 pathway have demonstrated similar clinical activity in treatment of NSCLC both for squamous(SCC) and non-squamous carcinoma (non-SCC) patients, the predictive role of PD-L1 expression is distinct between two histologies in clinical trials. In order to investigated the expression and prognostic roles of PD-1/PD-L1, data from TCGA and GEO database were analyzed and further validated with our original data by IHC in 133 resected NSCLC tumor tissue(49 SCC and 84 non-SCC). Through the analysis of online data, we concluded that PD-L1 expression in SCC was significantly higher than that of non-SCC. In addition, in non-SCC, PD-L1 was associated with immune response and indicated worse prognosis while no such results were observed in SCC. Further, our original data demonstrated PD-L1 expression in tumor cells(TC) and immune cells(IC) were significantly more often and more intense in SCC(P&amp;lt;0.001). In survival analysis, PD-L1 expression in TC and IC were associated with shorter overall survival in non-SCC (P=0.019 and 0.003, respectively). However, in SCC, PD-L1 did not demonstrate any significant effect neither in TC or IC (P=0.526 and 0.674, respectively) which consistent with online data. Contrary to PD-L1, no significant differences of PD-1 expression in tumor infiltrating lymphocytes(TILs) were showed between two histologies. PD-1 in TILs of SCC correlated with worse prognosis (P=0.025) while in non-SCC there was no correlation(P=0.986). Taken together, these findings suggest distinct regulation mechanisms and clinical significance of PD-L1/PD-1 pathway in NSCLC subgroups. Citation Format: Yunpeng Liu, Shuo Wang, Xiujuan Qu, Zhi Liu, Xiaofang Che, Xu Ling, Kezuo Hou, Yibo Fan, Na Song, Ti Wen, Ce Li. Different expression and prognostic effect of PD-L1/PD-1 in SCC and non-SCC of non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3989. doi:10.1158/1538-7445.AM2017-3989