Overexpression of FAM3C is associated with poor prognosis in oral squamous cell carcinoma

Expression of the family with sequence similarity 3 member C (FAM3C) is necessary for the epithelial-mesenchymal transition (EMT). However, the expression level and clinicopathological significance of FAM3C in oral squamous cell carcinoma (OSCC) has not been thoroughly elucidated to date. We performed immunohistochemical staining on human OSCC specimens with FAM3C, co-inhibitory immune checkpoints, EMT markers, and cancer stem cells (CSCs) markers to analyze the expression levels and clinicopathological features of FAM3C in OSCC. There were 210 primary OSCC specimens, 69 oral epithelial dysplasia and 42 normal oral mucosae in our human OSCC tissue microarrays cohort. We observed that FAM3C expression was upregulated in OSCC compared with normal mucosa and epithelial dysplasia (P?<? 0.001). Moreover, patients with higher FAM3C expression levels had a worse prognosis than those with lower expression levels (P < 0.05). Also, FAM3C expression was positively correlated with the immune checkpoints PD-L1, VISTA, and B7-H4, the EMT marker Slug and the CSC markers SOX2 and ALDH1. In conclusion, these findings suggested that overexpression of FAM3C in human OSCC may predict a poor prognosis for OSCC patients.     

CD8+ and CD163+ infiltrating cells and PD‐L1 immunoexpression in oral leukoplakia and oral carcinoma

Overexpression of inhibitory checkpoint PD1/PD‐L1 plays an important role in carcinogenesis and patients prognosis. 70 cases of oral squamous cell carcinoma (OSCC), 23 cases of oral leukoplakia (OLK), and 19 control cases were immunohistochemically stained with anti‐PD‐L1, ‐CD8, and ‐CD163 antibodies. PD‐L1 was expressed on dysplastic and subepithelial infiltrating cells of OLK as well as on cancer and tumor‐infiltrating cells of OSCC. In OSCC, PD‐L1 immunoexpression was significantly increased in comparison to OLK, and control groups. The correlative study showed significant correlations between the immunoexpression of PD‐L1 and the number of CD8+, CD163+ cells in both OLK and OSCC groups. We found also significant negative correlation between the number of PD‐L1+ infiltrating cells and the number of CD8+ cells in OSCC, and positive correlation between the number of PD‐L1+ infiltrating cells and CD163+ cells in OLK and OSCC groups. In conclusion, our study indicate that CD163+ and CD8+ infiltrating cells influence the early and subsequent stages of oral carcinogenesis. We demonstrated also that studied tumors may evade the host immune system by PD‐L1 immunoexpression not only on epithelial cells but on infiltrating cells as well.     

Aurora-B expression and its correlation with cell proliferation and metastasis in oral cancer

Aurora-B kinase is a chromosomal passenger protein and is essential for chromosome segregation and cytokinesis. Aurora-B overexpression in various cancer cells induces chromosomal number instability to produce multinuclearity and relates to metastasis. Here, we examined the expression of Aurora-B in oral squamous cell carcinoma (OSCC) to elucidate the relationship between Aurora-B expression and clinico-pathological findings by immunohistochemistry. Aurora-B expression was observed in normal oral squamous epithelia and OSCC cases, but the number of positive cells was significantly higher in OSCC than in normal squamous epithelium (p < 0.01). The labeling index of Aurora-B was significantly correlated with lymph node metastasis (p < 0.01) and histological grades of differentiation (p < 0.01). We also compared Aurora-B expression with Ki-67 expression and a positive correlation was found (p < 0.0001). Moreover, Aurora-B expression is significantly more frequent in multinuclear tumor cells than in total tumor cells. In summary, we found that Aurora-B expression was well correlated with cell proliferation, induction of multinuclear cells, histological differentiation, and metastasis in OSCC. These findings suggest that Aurora-B may be involved in tumor progression and that Aurora-B can be a new diagnostic and therapeutic target for OSCC.     

NOD1, RIP2 and Caspase12 are potentially novel biomarkers for oral squamous cell carcinoma development and progression

Although increasing studies have indicated that Nucleotide-oligomerization domain-containing protein 1 (NOD1) signaling could play an important role in gastrointestinal tumorigenesis, the protein expression and function of NOD1 signaling have not been understood well in oral squamous cell carcinoma (OSCC) progression. The objective of this study is, thus, to examine protein expression of NOD1 signaling immunohistochemically in normal, premalignant and malignant specimens of oral cavity, and to take insights into the association between the protein expression of NOD1 signaling pathway and OSCC precession. In this study immunohistochemical expression of NOD1, Receptor-interacting protein 2 (RIP2), Caspase12, human β Defensin1, 2 and 3 (hBD1, 2, 3) was examined in 15 normal controls, 30 cases of oral leukoplakia (OLK) and 60 cases of OSCC. The immunostaining score was assessed by 2 pathologists, respectively. We found that the expression of NOD1, RIP2, Caspase12, hBD1, 2, and 3 decreased along with the progression of OSCC. NOD1 expression was correlated significantly to tumor differentiation, lymph node metastasis, and tumor size. Our results also showed the correlation of hBD2, 3 to lymph node metastasis of OSCC. These results suggest that the dysfunction of NOD1 signaling pathways could be associated with OSCC development and progression. NOD1, RIP2 and Caspase12 could be used as potentially novel biomarkers for oral carcinogenesis.     

Oral squamous cell carcinoma suppressed antitumor immunity through induction of PD-L1 expression on tumor-associated macrophages

Oral squamous cell carcinoma (OSCC) is the most common solid tumor in the oral cavity. Development and progression of OSCC is associated with the elevated presence of inhibitory M2 type tumor-associated macrophages (TAMs). However, the underlying mechanism leading to the enrichment of M2 TAMs and the pathway through which TAMs foster tumor progression are still unclear. In this study, we harvested TAMs and tumor cells from primary OSCC resections of stage II and stage III patients. We showed that compared to peritumoral macrophages, TAMs presented upregulated expression of PD-L1 and elevated capacity in inducing T cell apoptosis. The level of PD-L1 expression directly correlated with the level of T cell apoptosis. Interestingly, peripheral blood monocytes with low initial PD-L1 level had upregulated PD-L1 expression and acquired the ability to induce T cell apoptosis, after incubation with primary tumor cells from OSCC patients. The PD-L1 expression by monocytes depended on interleukin 10 (IL-10), since blockade of IL-10 in the tumor-monocyte coculture abrogated PD-L1 upregulation. IL-10 mRNA expression in tumor cells and monocytes also preceded PD-L1 mRNA expression in monocytes. Furthermore, the IL-10 concentration in the tumor microenvironment directly correlated with the PD-L1 level on TAMs. Together, these results suggest that OSCC could directly suppress antitumor T cell immunity through conditioning TAMs.     

Immunosuppressive mediators of oral squamous cell carcinoma in tumour samples and saliva

The goal of this study was to compare the salivary concentrations of IL-10, TGF-β1 and soluble HLA-G (sHLA-G) in patients with oral squamous cell carcinoma (OSCC) to those in healthy individuals (control group), and to correlate the expression of these mediators in saliva with that in the tumour microenvironment. Neoplastic tissue and saliva samples from patients with OSCC (n = 22) were analysed by immunohistochemistry and enzyme-linked immunosorbent assay (ELISA) respectively. We detected high expression of IL-10 and HLA-G in the tumour microenvironment when compared to healthy oral mucosa samples. Determination of IL-10 salivary concentration enabled us to distinguish patients with OSCC from healthy individuals (P = 0.038), which showed correlation with tissue expression of this cytokine. HLA-G salivary release was similar in both groups (P = 0.17) and no correlation with tumour expression was observed. TGF-β1 expression was low or absent in tumours, and salivary concentration was similar between groups. Our results suggest that of the three markers analysed, IL-10 is a potential salivary biomarker. Furthermore, the elevated expression of HLA-G and IL-10 in tumour sites could favour the escape of tumour cells from immune defense mechanisms.     

Expression of E-cadherin and vimentin in oral squamous cell carcinoma

The aim of the study is to determine the levels of E-cadherin, vimentin expression in tumor tissues from patients with oral squamous cell carcinoma (OSCC), and the relationship between the expression of E-cadherin, vimentin and epithelial-mesenchymal transition, in order to explore its values for predicting the invasion and metastasis of oral squamous cell carcinoma, short survival of patients in many types of cancer. E-cadherin and vimentin expression of 10 benign and 42 OSCC tumor tissues was examined by immunohistochemical staining. E-cadherin is positively expressed in normal oral mucosa epithelium, but vimentin expression is not found in normal oral mucosa epithelia; the E-cadherin and vimentin were expressed in 26 of 42 (61.9%) and 16 of 42 (38.1%), respectively. No statistically difference was found for E-cadherin and vimentin expression in patients with different age, gender and tumor location, E-cadherin and vimentin expression was significantly associated with lymph node metastasis and tissue location (P < 0.05); E-cadherin expression was also significantly associated with tumor stage (P < 0.05); there are significantly difference between infiltrative margin and central area in patients with oral squamous cell carcinoma for E-cadherin and vimentin positive expression (P < 0.05). E-cadherin and vimentin positive expression was associated with tumor metastasis of oral squamous cell carcinoma. Our study preliminarily confirmed that EMT phenomenon is existed during the development of oral squamous cell carcinoma. Co-evaluation of E-cadherin and vimentin might be a valuable tool for predicting OSCC patient outcome.     

CD44v6与MMP—9在口腔鳞癌中的表达意义

目的：探讨细胞粘附分子CD44v6和基质金属蛋白酶MMP－9相互关系及其在评估口腔鳞癌的组织学分级,肿瘤浸润以及转移等生物学特性中的意义。方法：运用免疫组化S－P法测定22例口腔鳞癌和6例正常口腔黏膜组织中CD44v6和MMP－9的表达,结果：CD44v6在正常口腔黏膜组织呈强阳性表达;癌组织中CDv6的表达明显弱于正常组织,高表达CD44v6的口腔鳞癌不仅分化程度较差而且易发生淋巴结转移,MMP－9在正常口腔黏膜组织中呈阴性或弱阳性表达,癌组织中MMP－9的阳性表达高达68．2％（15／22）。MMP－9的表达与病理分级和颈淋巴结转移呈正相关（P＜0．05）,口腔鳞癌中MMP－9与CD44v6的表达呈正相关（P＜0．01）,多因素分析示两者之间的交互作用是影响口腔鳞癌病理分化和颈淋巴结转移的最重要因素。结论：口腔鳞癌中CD44v6与MMP－9的表达密切相关。MMP－9和CD44v6可作为临床上评估口腔鳞癌浸润,转移以及预后的指标。     

新疆地区口腔鳞状细胞癌中PLCE1蛋白的表达及临床意义

目的探讨PLCE1蛋白在新疆地区口腔鳞状细胞癌(oral squamous cell carcinoma,OSCC)中的表达及预后价值。方法采用免疫组化EnVision两步法检测124例OSCC及63例癌旁正常组织中PLCE1蛋白的表达,分析其表达与OSCC临床病理特征及预后的关系。结果OSCC及癌旁组织中PLCE1蛋白高表达率分别为41.9%(52/124)和0(0/63),差异有统计学意义(P<0.0001)。PLCE1诊断OSCC的ROC曲线下面积(AUC)为0.954(敏感度83.9%,特异性95.2%)。Kaplan-Meier及Cox单因素分析显示,PLCE1高表达(P=0.004、P=0.006)和T分期(P=0.002、P=0.004)是影响患者不良预后的危险因素。Cox多因素分析结果显示,PLCE1高表达(P=0.008)和T分期(P=0.005)是患者预后的独立因素。结论PLCE1蛋白在新疆地区OSCC组织中高表达,且与患者不良预后相关,可作为肿瘤患者不良预后的新型生物标志物。     

Tumor mutation burden,DNA mismatch repair status and checkpoint immunotherapy markers in primary and relapsed malignant rhabdoid tumors

IntroductionMalignant rhabdoid tumor (MRT) is a rare, aggressive pediatric tumor of nuclear lineage. It is mainly characterized by germline or somatic SMARCB1 (INI1) driver mutations. To characterize the potential for immunotherapy in untreated and treated MRT, current study investigated tumor mutational burden (TMB) and other biomarkers in MRT.Material and methodsNormal-tumor paired whole exome sequencing (WES) and/or immunohistochemistry (IHC) of DNA mismatch repair (MMR) proteins, PD-L1, PD-1 and CD8 were performed in 16 cases, some with both primary and relapsed tumor.ResultsFive cases subjected to WES demonstrated germline SMARCB1 (INI1) mutations. TMB was 0.7–1.07/Mb in 4 of the 5 primary untreated tumors, and 33.81/Mb in one case with pathogenic MMR, POLD, and POLE mutations. Ten cases tested for MMR status by IHC showed retained nuclear expression of the proteins. Eight of the 16 cases (8/16, 50%) showed membranous expression of PD-L1 in 10–70% of tumor cells (tumor proportion score, TPS). Nine cases (9/16, 56.3%) showed high (>2/HPF) tumor infiltrating lymphocytes with PD-1 staining ranging 10–60%, correlating with tumor PD-L1 staining (p < 0.0001). Between post-treatment metastatic tumors and the pre-treatment primary tumors, TMB was similar while PD-L1 TPS was similar or lower.ConclusionMRT has a low TMB. Nonetheless, because a subset of MRT cases have a PD-L1 TPS greater than the cutoff for checkpoint therapy in other malignancies, the utility of immune checkpoint inhibitors should be studied in this patient population.     

口腔鳞状细胞癌细胞周期蛋白E表达与中心体扩增相关性

目的了解口腔鳞状细胞癌细胞周期蛋白E（cyclin E）表达与中心体扩增相关性,探讨其中心体扩增的可能分子机制。方法正常口腔黏膜组织12例,不同分化程度的口腔鳞状细胞癌46例石蜡包埋组织,采用间接免疫荧光双重染色（γ-微管蛋白单克隆抗体及细胞角蛋白多克隆抗体）观察口腔鳞状细胞癌中心体扩增状况;采用免疫组织化学（SABC法）检测相应组织cyclin E蛋白表达情况,分析cyclin E蛋白表达与中心体扩增之间的相关性。结果中心体扩增可见于80．4％（37／46）口腔鳞状细胞癌组织中,而cyclin E蛋白过表达可在65．2％（30／46）的口腔鳞状细胞癌组织中见到;中心体扩增发生率在cyclin E阳性组为90．0％（27／30）,而在cyclin E蛋白阴性组为10／16,两组间差异有统计学意义（x^2=5．014,P〈0．05）;Spearman相关分析显示中心体扩增与cyclin E蛋白阳性表达间存在相关关系（r=0．330,P〈0．05）;绝对危险度分析OR值为5．400（1．130,25．809）。结论肿瘤细胞中心体循环调控可能是一个多因素参与的复杂过程,cyclin E蛋白表达的高调作为危险因素之一可能在口腔鳞状细胞癌中心体扩增中起一定作用。     

表皮生长因子受体在口腔鳞癌组织中的表达及意义

目的：研究表皮生长因子受体（ＥＧＦＲ）在口腔鳞癌组织中的表达及其临床病理学意义。方法：采用免疫组化Ｓ－Ｐ法对６５例不同分化的口腔鳞癌组织及１０例正常口腔粘膜组织进行ＥＧＦＲ检测。结果：ＥＧＦＲ在鳞癌组织中呈异质性表达,其阳性率（６１．５％）明显高于正常口腔粘膜组织（Ｐ〈０．０１）;ＥＧＦＲ表达状况与鳞癌组织学分级,区域淋巴结转移及患者预后间存在相关关系（Ｐ〈０．０１或０．０５）。结论：ＥＧＦＲ在口     

High expression of stathmin 1 is a strong prognostic marker in oral squamous cell carcinoma patients treated by docetaxel-containing regimens

Stathmin 1 is an oncoprotein that regulates cell cycle by modulating microtubule dynamics and can cause uncontrolled cell proliferation in mutated state. The present study examined stathmin 1 expression in 49 patients with oral squamous cell carcinoma (OSCC) treated with docetaxel (Doc)-containing regimens by immunohistochemical staining. Moreover, we investigated the relationship between stathmin 1 expression and clinicopathological features, as well as the prognosis of above patients. Stathmin 1 could be detected in the cytoplasm of tumor cells in OSCC tissues though its expression level was variable. There was no correlation between stathmin 1 expression and patient gender, or age in OSCC. However, stathmin 1 expression of tumor cell was significantly correlated with T classification (P = 0.0017), N classification (P = 0.0171), stage (P < 0.0001), therapeutic efficacy (P < 0.0001), and patient outcome (P = 0.0387). In addition, high expression of stathmin 1 in tumor cells was associated with shorter overall survival (OS, P = 0.0017). Multivariate analysis also revealed that high expression of stathmin 1 was a predictor of reduced survival (P = 0.0241). These findings suggest that patients with OSCC tumors showing high expression of stathmin 1 might have poor therapeutic effects and worse clinical outcomes in OSCC treated with Doc-containing regimen.     

Overexpression of immunomodulatory mediators in oral precancerous lesions

Human leukocyte antigen (HLA) G and E, programmed cell death 1 ligand 1 (PD-L1), IL-10 and TGF-β are proteins involved in failure of the antitumor immune response. We investigated the expression of these immunomodulatory mediators in oral precancerous lesions (oral leukoplakia-OL; n = 80) and whether these molecules were related to the risk of malignant transformation. Samples of normal mucosa (n = 20) and oral squamous cells carcinoma (OSCC, n = 20) were included as controls. Tissue and saliva samples were analyzed by immunohistochemistry and ELISA respectively. Fifteen OL samples showed severe dysplasia (18.7%) and 40 samples (50%) presented combined high Ki-67/p53. Irrespective of the degree of epithelial dysplasia and the proliferation/apoptosis index of OL, the expression of HLA-G, -E, PD-L1, IL-10, TGF-β2 and -β3 was higher to control (P < 0.05) and similar to OSCC (P > 0.05). The number of granzyme B⁺ cells in OL was similar to control (P = 0.28) and lower compared to OSCC (P < 0.01). Salivary concentrations of sHLA-G, IL-10 and TGF-β did not allow for a distinction between OL and healthy individuals. Overexpression of immunosuppressive mediators in the OL reflects the immune evasion potential of this lesion, which is apparently independent of at cytological and proliferation/apoptosis status.     

High expression of TROP2 is correlated with poor prognosis of oral squamous cell carcinoma

Human trophoblastic cell-surface antigen 2 (TROP2) is a cell surface glycoprotein that exhibits high expression in various carcinomas but low or no expression in normal tissues. High TROP2 expression plays an important role in promoting tumor development and aggressiveness, which is correlated with reduced patient survival. However, there are few studies regarding TROP2 in relation to both oral squamous cell carcinoma (OSCC) and oral potentially malignant lesions. The expression of TROP2 protein and mRNA was investigated in OSCC tissues, oral potentially malignant lesion tissues, and normal oral tissues using immunohistochemistry and quantitative real-time polymerase chain reaction (qRT-PCR). The association between TROP2 expression and clinicopathological characteristics of OSCC was also analyzed, and the prognostic value of TROP2 was evaluated. The expression of TROP2 protein and mRNA were both higher in OSCC tissues than in oral potentially malignant lesion tissues or normal oral tissues. Positive TROP2 expression was related to differentiation, lymph node metastases, TNM stage, perineural infiltration, and vascular invasion. Poor overall survival was associated with high TROP2 expression and other factors associated with poor overall survival including poor differentiation, lymph node metastasis, TNM stage, vascular invasion, and perineural invasion in univariate analyses. TROP2 expression as well as TNM stage and vascular invasion were independent prognostic factors associated with the overall survival of OSCC patients in multivariate analyses. In summary, High TROP2 expression is associated with poor overall survival and serves as an independent prognostic factor in OSCC. The results suggest that TROP2 expression could be an effective prognostic biomarker for OSCC.     

Nicotine promotes the development of oral leukoplakia via regulating peroxiredoxin 1 and its binding proteins

Tobacco can induce reactive oxygen species (ROS) production extensively in cells, which is a major risk factor for oral leukoplakia (OLK) development. Peroxiredoxin 1 (Prx1) is a key antioxidant protein, upregulated in a variety of malignant tumors. We previously found that nicotine, the main ingredient of tobacco, promotes oral carcinogenesis via regulating Prx1. The aim of the present study was to screen and identify the Prx1 interacting proteins and investigate the mechanisms of nicotine on the development of OLK. Through liquid chromatography-tandem mass spectrometry combined with bioinformatics analysis, the candidate Prx1 interacting proteins of cofilin-1 (CFL1), tropomyosin alpha-3 chain (TPM3), and serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform (PPP2R1A) were screened in human dysplastic oral keratinocyte cells treated with nicotine. CFL1, TPM3, and PPP2R1A were highly expressed in human OLK tissues. The expression of CFL1 increased and the expression of PPP2R1A decreased in OLK of smokers compared to that in OLK of non-smokers. Nicotine upregulated CFL1 and downregulated PPP2R1A in 4-nitro-quinoline-1-oxide (4NQO)-induced OLK tissues in mice in part dependent on Prx1. Furthermore, the in-situ interaction of CFL1, TPM3, and PPP2R1A with Prx1 were validated in human OLK tissues. Our results suggested that tobacco might promote the development of OLK via regulating Prx1 and its interacting proteins CFL1 and PPP2R1A.     

The expression of C-MYC in gastric adenocarcinoma is associated with PD-L1 and FOXP3 expression: C-MYC overexpression is a good prognostic factor

BackgroundC-MYC appears to initiate and maintain tumorigenesis through modulation of immune regulatory molecules such as PD-L1. The aim of our research was to evaluate the clinical implication of C-MYC expression in gastric adenocarcinoma in relation to the expression of the immune regulatory molecules PD-L1 and FOXP3.MethodsTissue samples were acquired from 182 cases of gastric adenocarcinoma that were surgically resected at Kyung Hee University Hospital at Gangdong from 2006 to 2012. Immunohistochemical staining for C-MYC, PD-L1, CD8 and FOXP3 was done.ResultsC-MYC overexpression showed a significant correlation with smaller tumor size, lower T category, lower N category, lower recurrence rate, and less lymphatic invasion. And C-MYC overexpression was negatively correlated with PD-L1 expression. The tumoral FOXP3 was positively correlated with C-MYC overexpression and Tregs count. PD-L1 expression was positively correlated with Tregs, CD8 + T cells, and tumor infiltrating lymphocytes (TIL). Tregs count was positively correlated with CD8 + T cells and TIL. CD8 + T cells was positively correlated with TIL.ConclusionWe discovered that the immune regulatory effect of C-MYC and PD-L1, and the tumor suppressor function of tumoral FOXP3 had a significant influence on the tumor microenvironment (Tregs, CD8 + T cells, and tumor infiltrating lymphocytes) in a complex manner. The C-MYC overexpression is a good prognostic factor in gastric adenocarcinoma.     

High PD-L1 expression in gastric cancer (GC) patients and correlation with molecular features

BackgroundThe programmed death receptor ligand 1 (PD-L1) immunohistochemistry (IHC) 22C3 pharmDx assay is a widely used selection method for pembrolizumab treatment in gastric cancer (GC) patients, especially in the U.S. The present study investigated the relationship between PD-L1 expression and the clinical features, molecular markers, and molecular subtypes of GC.MethodsPD-L1 expression was assessed based on combined positive score (CPS) using PD-L1 IHC 22C3 pharmDx in the Asian Cancer Research Group (ACRG) GC cohort (N = 300), which has been previously genomically profiled. PD-L1 positivity was defined as PD-L1 CPS ≥ 1. The association between PD-L1 expression and clinical features, tumor burden, and molecular subtypes (ACRG and The Cancer Genome Atlas [TCGA]) was analyzed.ResultsOf the 300 tumors, 178 (59.3 %) had PD-L1 CPS ≥ 1 and 122 (40.7 %) had PD-L1 CPS < 1. PD-L1 CPS ≥ 1 was significantly associated with stage I tumor (P = 0.022), high microsatellite instability (MSI-H) (P < 0.001), Epstein-Barr virus (EBV) positivity (P = 0.008), and positive Helicobacter pylori status (P = 0.001). PD-L1 CPS ≥ 1 was observed in 96/193 (49.7 %) EBV-negative/microsatellite stable (MSS) tumors. In gene expression profiling, PD-L1 CPS was highly correlated with mutational load (P < 0.001) as well as EBV (P < 0.001) and MSI subtypes (P < 0.001); 27/300 (9%) GC patients had a very high PD-L1 (≥ 20) score (MSI-H, n = 10; EBV, n = 6; and non-EBV/MSS, n = 11). OS was longer in patients with PD-L1 CPS ≥ 1 tumors than in those with PD-L1 CPS < 1 tumors (median OS not reached vs. 40 months; P = 0.008; log-rank test).ConclusionsPD-L1 is expressed in 59.3 % of GC patients and is associated with MSI and EBV positivity. These results provide a basis for identifying GC patients who may benefit from anti-PD-1/PD-L1 therapy.