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PD-L1 expression and outcome. PD-L1 expression correlates with overall survival of HNSCC patients. All patients had a localized or locally advanced disease and were treated with curative intent. (A) first HNSCC cohort (p<0.004), (B) second HNSCC cohort (p<0.0001).
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Background:
The PD-1 receptor and its ligands PD-L1 and PD-L2 are known to be significantly involved in T-cell regulation. Recent studies suggest that PD-L1 expression in malignant tumors contributes to an immunosuppressive microenvironment and disruption of antitumoral immune response. Drugs targeting this pathway are already tested in clinical t...
Contexts in source publication
Context 1
... found a strong correlation between PD-L1 expression and overall survival in both the first (p<0.004, Figure 2) and the second (p<0.0001, Figure 2 In a multivariate cox proportional hazards model, high expression of PD-L1 prevailed to be an independent and in fact the strongest prognostic factor of patient's outcome, even when verified together with recognized prognostic factors like tumor size, lymph node involvement, distant metastases, surgical margin status, lymphatic invasion, vascular invasion, grading, and extracapsular expansion (p=0.02; HR=2.926 [95%CI=1.183 ...
Context 2
... 2) and the second (p<0.0001, Figure 2 In a multivariate cox proportional hazards model, high expression of PD-L1 prevailed to be an independent and in fact the strongest prognostic factor of patient's outcome, even when verified together with recognized prognostic factors like tumor size, lymph node involvement, distant metastases, surgical margin status, lymphatic invasion, vascular invasion, grading, and extracapsular expansion (p=0.02; HR=2.926 [95%CI=1.183 ...
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Uveal melanoma is the most common primary intraocular malignancy among adults. It is, nevertheless, a rare disease, with an incidence of approximately one case per 100,000 individuals per year in Europe. Approximately half of tumors will eventually metastasize, and the liver is the organ usually affected. No standard-of-care treatment...
Citations
... As patients respond to chemotherapy clinically, it is more probable to see a decrease in PD-L1 expression. There is no any association between the increase in PD-L1 expression and the patient's clinical presentation [172] . There are two different possible patterns of PD-L1 expression: diffuse and marginal, which are seen in cervical squamous cell carcinoma and cervical adenocarcinoma, respectively. ...
Aim: Cancer as a complex disease poses significant challenges for both diagnosis and treatment. Researchers have been exploring various avenues to find effective therapeutic strategies, with a particular emphasis on cellular signaling pathways and immunotherapy. One such pathway that has recently been suggested is the PD-1/PD-L1 pathway, which is an immune checkpoint signaling system that plays an important role in regulating the immune system and maintaining tissue homeostasis. Cancer cells exploit this pathway by producing PD-L1, which attaches to PD-1 on T cells, thus inhibiting immune responses and enabling the cancer cells to escape detection by the immune system. This study aimed to evaluate the role of the PD-1/PD-L1 pathway in cancer pathogenesis and
... HNSCC is known to have immunosuppressive activity; however, significance of PD-L1 expression in HNSCC is still not fully elucidated, unlike in other malignancies. [3] Most patients of HNSCC receive aggressive multimodal therapeutic regimens consisting of combinations of radiation, chemotherapy and surgery. [4,5] PDL1 is a promising novel predictive biomarker identified in cancer immunotherapy. ...
... [6] However, comprehensive data about its expression in HNSCC and therefore a rational basis for antiPDL1/PD1 therapy is lacking. [3] In 2019, the US Food and Drug Administration (FDA) approved pembrolizumab as first-line treatment for patients with Recurrent/Metastatic HNSCC. [7] FDA also approved a companion diagnostic device for measuring the combined positive score (CPS) by using PD-L1 immunohistochemistry (IHC) 22C3 pharmDx kit, to select patients for pembrolizumab monotherapy. ...
... These observations coincide with previous studies. [3,8,14] However, a few studies showed high PD-L1 expression in OSCC compared to OPSC, HPSC and LSC. [8] No significant influence on the differentiation of tumour/ lymph node metastasis/early tumour stages (T1/2) versus late tumour stages (T3/4) on the expression pattern of PD-L1 could be observed in the present study. ...
Context
Programmed cell death ligand 1 (PD L1) is a transmembrane protein that is highly expressed in neoplastic cells. Therapy with immune checkpoint inhibitors target PD-1/PD-L1 blockade-inducing tumour regression. Immunohistochemistry (IHC) for PD-L1 expression enables patient selection for immunotherapy and can be considered as a potential predictive biomarker for immunotherapy in head and neck squamous cell carcinoma (HNSCC).
Aims
To determine the PDL1 expression in HNSCC, to correlate with clinicopathological features and outcome.
Settings and Design
We retrospectively analysed 59 cases of HNSCC at our Tertiary Hospital between January 2017 and November 2018 and followed up until death/Nov 2022 for Overall survival.
Methods and Material
IHC analysis of PD-L1 using Combined Positive Score (CPS) with antibody clone 22C3 in 59 cases of HNSCC was performed. PD-L1 expression was correlated with clinicopathological features and outcomes.
Statistical Analysis Used
Pearson Chi-square test was used to analyse the correlation between PD-L1 expression and clinicopathological parameters using SPSS20.0. Survival curves were calculated by Kaplan–Meier method, and differences were analysed by log-rank test.
Results
A total of 25 cases (42.4%) had positive PDL expression (CPS ≥1). 16/25 cases (27.1%) belonged to CPS (≥1, <10). An almost-perfect interobserver agreement was noted by two pathologists for PD-L1 IHC expression. No statistically significant correlation was noted between PD-L1 score and clinicopathologic features.
Conclusions
Detection of PD-L1 status gives further insight into frequency of PD-L1 expression in Indian HNSCC patients to possibly improve clinical treatment strategies, ensuring that our patients get the maximum therapeutic benefit of immunotherapy.
... However, other studies found that the increased expression of PD-L1 was associated with longer disease-free survival in high-risk head and neck squamous cell carcinoma [107]. Limitations to the use of PD-L1 include its unknown significance in head and neck squamous cell carcinoma apart from oral cavity cancer, and the lack of data on the PD-L1 ligand in head and neck squamous cell carcinoma [108]. ...
Head and neck cancers (HNC) are a biologically diverse set of cancers that are responsible for over 660,000 new diagnoses each year. Current therapies for HNC require a comprehensive, multimodal approach encompassing resection, radiation therapy, and systemic therapy. With an increased understanding of the mechanisms behind HNC, there has been growing interest in more accurate prognostic indicators of disease, effective post-treatment surveillance, and individualized treatments. This chapter will highlight the commonly used and studied biomarkers in head and neck squamous cell carcinoma.
... The significance and impact of sPD-L1 expression on clinicopathological characteristics and its predictability are currently under debate among researchers [16][17][18]. While some studies suggest that PD-L1expressing HNSCC leads to unfavorable clinical outcomes [17,19], others propose that it results in increased survival [20,21]. ...
... The significance and impact of sPD-L1 expression on clinicopathological characteristics and its predictability are currently under debate among researchers [16][17][18]. While some studies suggest that PD-L1expressing HNSCC leads to unfavorable clinical outcomes [17,19], others propose that it results in increased survival [20,21]. Malignant cells from various types of cancer, such as lung, breast, and renal cell carcinomas, have been found to exhibit high levels of PD-L1 expression. ...
Background and objective
Head and neck squamous cell carcinoma (HNSCC) is a prevalent cancer type that affects the mucosal lining of the upper aerodigestive tract. Soluble programmed death-ligand 1 (sPD-L1) is a significant factor in hindering T cells' function, which prevents cancer cells from being detected by the immune system. This means that sPD-L1 is an essential component in the immune evasion of cancer. This study aimed to explore the potential of sPD-L1 as a prognostic biomarker for patients with HNSCC undergoing concurrent chemotherapy and radiation therapy.
Methodology
The study included 106 patients with locally advanced HNSCC who received three courses of induction chemotherapy followed by concurrent chemoradiation and 60 healthy subjects as controls. sPD-L1 levels were measured using an enzyme-linked immunosorbent assay (ELISA) kit, and the cutoff value was determined based on receiver operating characteristic (ROC) curve analysis.
Results
The results showed that sPD-L1 levels were significantly higher in HNSCC patients compared to healthy controls, with a cutoff value of 31.51 pg/mL. Higher sPD-L1 levels were associated with poorer overall survival rates.
Conclusions
These findings suggest that sPD-L1 may serve as a valuable prognostic biomarker for HNSCC patients undergoing concurrent chemotherapy and radiation therapy. The study highlights the importance of exploring new biomarkers and therapeutic strategies for HNSCC to improve patient outcomes and reduce morbidity and mortality rates associated with this disease.
... PD-L1 appears to be a negative prognostic factor in NSCLC, yet remains controversially discussed (56). For HNSCC, a study indicates that tumors with high PD-L1 expression potentially follow an unfavorable clinical course (57), which is in line with other studies (58,59). In summary, patients whose tumors strongly express PD-L1 might benefit from the (early) application of CPI and it is likely to be advantageous to combine anti-PD (L)-1 agents with standard pillars. ...
Although checkpoint inhibitors (CPI) have recently extended the treatment options and improved clinical response of advanced stage head and neck squamous cell carcinoma (HNSCC), treatment success remains unpredictable. Programmed cell death ligand‑1 (PD‑L1) is a key player in immunotherapy. Tumor cells, and exosomes derived therefrom, are carriers of PD‑L1 and efficiently suppress immune responses. The aim of the present study was to analyze the influence of established therapies on PD‑L1 expression of HNSCC cell lines and their exosomes. The HNSCC cell lines, UM‑SCC‑11B, UM‑SCC‑14C and UM‑SCC‑22C were treated with fractionated radiotherapy (RT; 5x2 Gy), cisplatin (CT) and cetuximab (Cetux) as monotherapy, or combined therapy, chemoradiotherapy (CRT; RT and CT) or radioimmunotherapy (RT and Cetux). The expression of PD‑L1 and phosphorylated (p)ERK1/2 as a mediator of radioresistance were assessed using western blotting, immunohistochemistry and an ex vivo vital tissue culture model. Additionally, exosomes were isolated from concentrated supernatants of the (un‑)treated HNSCC cell lines by size exclusion chromatography. Exosomal protein expression levels of PD‑L1 were detected using western blotting and semi‑quantitative levels were calculated. The functional impact of exosomes from the (un‑)treated HNSCC cell lines on the proliferation (MTS assay) and apoptosis (Caspase 3/7 assay) of the untreated HNSCC cell lines were measured and compared. The HNSCC cell lines UM‑SCC‑11B and UM‑SCC‑22B showed strong expression of pERK1/2 and PD‑L1, respectively. RT upregulated the PD‑L1 expression in UM‑SCC‑11B and UM‑SCC‑14C and in exosomes from all three cell lines. CT alone induced PD‑L1 expression in all cell lines. CRT induced the expression of PD‑L1 in all HNSCC cell lines and exosomes from UM‑SCC‑14C and UM‑SCC‑22B. The data indicated a potential co‑regulation of PD‑L1 and activated ERK1/2, most evident in UM‑SCC‑14C. Exosomes from irradiated UM‑SCC‑14C cells protected the unirradiated cells from apoptosis by Caspase 3/7 downregulation. The present study suggested a tumor cell‑mediated regulation of PD‑L1 upon platinum‑based CRT in HNSCC and in exosomes. A co‑regulation of PD‑L1 and MAPK signaling response was hypothesized.
... Similarly, Moratin et al. concluded that elevated PD-L1 expression in human oral squamous cell carcinomas was correlated with tumor size, stage, regional metastases and worse OS [71]. On the other hand, Müller et al. found that PD-L1 expression in tumor tissue is correlated with better OS [72]. Other reports show that higher PD-1 and PD-L1 expression was associated with a better outcome with fewer local and distant recurrences, mainly in HPV-positive patients [73,74]. ...
Inflammation is an etiological factor of various chronic diseases contributing to more than 50% of worldwide deaths. In this study, we focus on the immunosuppressive role of the programmed death-1 (PD-1) receptor and its ligand (PD-L1) in inflammatory-related diseases, including chronic rhinosinusitis and head and neck cancers. The study included 304 participants. Of this number, 162 patients had chronic rhinosinusitis with nasal polyps (CRSwNP), 40 patients had head and neck cancer (HNC) and there were 102 healthy subjects. The expression level of the PD-1 and PD-L1 genes in the tissues of the study groups was measured by qPCR and Western blot methods. The associations between the age of the patients and the extent of disease and genes’ expression were evaluated. The study showed a significantly higher mRNA expression of PD-1 and PD-L1 in the tissues of both the CRSwNP and HNC patient groups compared to the healthy group. The severity of CRSwNP significantly correlated with the mRNA expression of PD-1 and PD-L1. Similarly, the age of the NHC patients influenced PD-L1 expression. In addition, a significantly higher level of PD-L1 protein was noticed also for both the CRSwNP and HNC patient groups. The increased expression of PD-1 and PD-L1 may be a potential biomarker of inflammatory-related diseases, including chronic rhinosinusitis and head and neck cancers.
... Therefore, it is important to understand the immune milieu of the disease and the role of cancer cells and other types of cells that regulates the immune response and cancer treatment. Accumulating evidence demonstrated the role of PD-L1 expression in patients' survival and treatment response [6,10,[27][28][29][30][31] but the role of PD-L1 / PD-1 in cancer initiation or recurrence is not known yet. In our study, we investigated PD-L1 expressions in ovarian cancer and its association with specific pathological and clinical outcomes, and the tumor microenvironment that include lymphocytes and cancer stem cell populations. ...
Background
Immune checkpoint inhibitors, including PD-L1 (programmed death ligand-1) inhibitors have well documented anticancer therapeutic effect in most types of cancers but its use in the treatment of ovarian cancer is not yet proven. The aim of our study is to explore the predictive biomarkers in ovarian cancer and its association with the outcomes. We have investigated the role of PD-L1 expressions in the tumor microenvironment cells including immune cells and cancer stem cells in different types of ovarian cancer.
Methods
A total of 119 surgical archived ovarian cancer samples were collected from the pathology department at King Fahad Specialist Hospital, Dammam, Saudi Arabia that included serous carcinomas, clear cell carcinomas, mucinous carcinomas, endometrioid carcinomas, and granulosa cell tumors. Immunohistochemistry (IHC) staining was performed using (i) PD-L1 antibodies to detect PD-L1 expressions; (ii) CD8 and CD4 to detect Tumor Infiltrating Lymphocytes (TILs); and (iii) CD44, LGR5, and ALDH2 to detect stem cell markers. The clinicopathological data were collected from patients’ medical record to investigate the association with PD-L1, TILs, and stem cells expressions.
Results
We report high PD-L1 expressions in 47.8% of ovarian cancer samples. PD-L1 expressions were detected in different types of epithelial ovarian cancer and were not associated with poor prognosis of ovarian cancer. However, determining the expression levels of TILs in the ovarian cancer tissues found that 81% ( n = 97) of ovarian cancer samples have TILs that express both of CD8 and CD4 and significantly associated with high PD-L1 expressions. Interestingly, we have found that ovarian cancer tissues with high expressions of PD-L1 were associated with high expressions of stem cells expressing CD44 and LGR5.
Conclusions
PD-L1 is highly expressed in the serous type of ovarian carcinomas and the overall expression of PD-L1 is not associated with poor survival rate. Furthermore, PD-L1 expressions are strongly associated with TILs and stem cell markers in ovarian cancer. Inhibiting the PD-L1 using immune checkpoint inhibitors might downregulate stem cell population that known to be associated with cancer recurrence.
... Genes and proteins related to HPV status, tumor hypoxia, the (anti-)tumoral immune system and cancer stem cells are examples of biomarkers that have been studied for HNSCC patients undergoing (chemo)radiotherapy [11][12][13][14][15]. Previous analyses and systematic meta-analyses have shown that higher levels of tumor-infiltrating lymphocytes (TILs), especially CD3 + and CD8 + TILs, are associated with improved survival in HNSCC patients receiving (chemo)radiotherapy [16][17][18][19][20][21][22][23]. In contrast, the prognostic role of immune checkpoints (ICs) for HNSCC patients undergoing radiotherapy is less clear [24][25][26][27][28][29][30][31]. Nevertheless, the tumoral PD-L1 status may become more relevant in the future considering clinical approaches combining (chemo)radiotherapy with IC inhibitors [32]. ...
... There are conflicting data regarding the prognostic value of tumoral PD-L1 expression in HNSCC [24][25][26][27][28][29][30][31]. Within a multicenter study of the German Cancer Consortium Radiation Oncology Group, Balermpas et al. showed a positive relationship between elevated PD-L1 expression and survival in locally advanced HNSCC patients treated by postoperative chemoradiotherapy [25]. ...
Background and purpose
Tumor-infiltrating lymphocytes (TILs) are associated with locoregional control (LRC) in head-and-neck squamous cell carcinoma (HNSCC) patients undergoing (chemo)radiotherapy. As immunosenescence results in reduced immune activity, the role of TILs in elderly HNSCC patients may differ compared to younger patients, providing a rationale to study the prognostic role of TILs and immune checkpoints (ICs) in this population.
Material and methods
Sixty-three HNSCC patients aged ≥ 65 years undergoing definitive (chemo)radiotherapy between 2010 and 2019 with sufficient material from pre-treatment biopsies were included in the analysis. Immunohistochemical stainings of CD3, CD4, CD8, PD-L1, TIM3, LAG3, TIGIT and CD96, and of osteopontin as an immunosenescence-associated protein were performed. Overall survival (OS) and progression-free survival (PFS) were determined using the Kaplan–Meier method, and Fine-Gray's models were used for locoregional failure (LRF) analyses.
Results
While there was no correlation between patient age and IC expression, osteopontin levels correlated with increasing age ( r = 0.322, p < 0.05). Two-year OS, PFS, and LRC were 44%, 34%, and 71%, respectively. Increased LAG3 expression, both intraepithelial (SHR = 0.33, p < 0.05) and stromal (SHR = 0.38, p < 0.05), and elevated stromal TIM3 expression (SHR = 0.32, p < 0.05) corresponded with reduced LRFs. Absent tumoral PD-L1 expression (TPS = 0%) was associated with more LRFs (SHR = 0.28, p < 0.05). There was a trend towards improved LRF rates in elderly patients with increased intraepithelial CD3 + (SHR = 0.52, p = 0.07) and CD8 + (SHR = 0.52, p = 0.09) TIL levels.
Conclusion
LAG3, TIM3 and TPS are promising biomarkers in elderly HNSCC patients receiving (chemo)radiotherapy. Considering the frequency of non-cancer related deaths in this population, the prognostic value of these biomarkers primarily relates to LRC.
... Primary samples were in that regard 88.5% EGFR-positive while relapsed samples were all EGFRpositive (Table 3, Figure 4A), limiting the ability to analyze EGFR on relapsed samples. In addition, tissue slides were also stained for PD-L1, as patient eligibility for pembrolizumab treatment is dependent on a PD-L1 CPS of at least 1 (31)(32)(33). We scored PD-L1 expression using both CPS and TPS, the latter which was used to maintain a uniform scoring. ...
Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous group of tumors that retain their poor prognosis despite recent advances in their standard of care. As the involvement of the immune system against HNSCC development is well-recognized, characterization of the immune signature and the complex interplay between HNSCC and the immune system could lead to the identification of novel therapeutic targets that are required now more than ever. In this study, we investigated RNA sequencing data of 530 HNSCC patients from The Cancer Genome Atlas (TCGA) for which the immune composition (CIBERSORT) was defined by the relative fractions of 10 immune-cell types and expression data of 45 immune checkpoint ligands were quantified. This initial investigation was followed by immunohistochemical (IHC) staining for a curated selection of immune cell types and checkpoint ligands markers in tissue samples of 50 advanced stage HNSCC patients. The outcome of both analyses was correlated with clinicopathological parameters and patient overall survival. Our results indicated that HNSCC tumors are in close contact with both cytotoxic and immunosuppressive immune cells. TCGA data showed prognostic relevance of dendritic cells, M2 macrophages and neutrophils, while IHC analysis associated T cells and natural killer cells with better/worse prognostic outcome. HNSCC tumors in our TCGA cohort showed differential RNA over- and underexpression of 28 immune inhibitory and activating checkpoint ligands compared to healthy tissue. Of these, CD73, CD276 and CD155 gene expression were negative prognostic factors, while CD40L, CEACAM1 and Gal-9 expression were associated with significantly better outcomes. Our IHC analyses confirmed the relevance of CD155 and CD276 protein expression, and in addition PD-L1 expression, as independent negative prognostic factors, while HLA-E overexpression was associated with better outcomes. Lastly, the co-presence of both (i) CD155 positive cells with intratumoral NK cells; and (ii) PD-L1 expression with regulatory T cell infiltration may hold prognostic value for these cohorts. Based on our data, we propose that CD155 and CD276 are promising novel targets for HNSCC, possibly in combination with the current standard of care or novel immunotherapies to come.
... PD-L1 expression of tumors is a key point in the use of ICIs such as PD-L1 inhibitors and PD-1 inhibitors. Several studies have shown that PD-L1 expression is associated with a good prognosis (30,31). For PET parameters, previous studies mainly investigated the positive correlation between SUV max and PD-L1 in other cancers (32)(33)(34). ...
Purpose
We evaluated baseline ¹⁸ F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) metabolic parameters for predicting prognosis in patients with head and neck squamous cell carcinoma (HNSCC) who were receiving immune checkpoint inhibitors (ICIs). In addition, we also investigated the relationships between immunohistochemical (IHC) biomarkers and metabolic parameters.
Materials and methods
A total of 39 patients with HNSCC who underwent ¹⁸ F-FDG PET/CT prior to ICI therapy between November 2015 and December 2020 were enrolled. PET parameters of tumor lesions included standardized uptake values, metabolic tumor volume (MTV), total lesion glycolysis (TLG), and spleen-to-liver ratio (SLR). Clinical variables, IHC markers, and derived neutrophil-to-lymphocyte ratio (dNLR) were also obtained. Analysis was performed using Cox proportional hazard model, Kaplan-Meier method with log-rank test, and Spearman's correlation.
Results
Total MTV (TMTV), total TLG (TTLG), and a combined parameter consisting of TMTV and dNLR were significant predictors for progression-free survival (PFS) in univariable analysis (TMTV, p = 0.018; TTLG, p = 0.027; combined parameter, p = 0.021). Above all, the combined parameter was an independent prognostic factor for PFS in multivariable analysis. The group with low TMTV and low dNLR had longer PFS than the group with high TMTV and high dNLR ( p = 0.036). SLR was the only significant predictor for overall survival ( p = 0.019). Additionally, there was a negative correlation between programmed cell death-ligand 1 expression (one of the IHC markers) and MTV in subgroup analysis.
Conclusion
PET parameters on baseline ¹⁸ F-FDG PET/CT were predictive biomarkers for prognosis in patients with HNSCC undergoing ICI therapy. With dNLR, more accurate prognostic prediction could be possible.
