Expression of immune-related molecules in primary EBV-positive Chinese nasopharyngeal carcinoma: associated with latent membrane protein 1 (LMP1) expression.
To understand the role of Epstein-Barr virus (EBV) and viral products in associated with immunophenotype and clinical outcome of primary nasopharyngeal carcinoma (NPC), the expression levels of chemokines IFN-g-induced protein 10 (IP-10, CXCL10), stromal-derived factor-1 (SDF-1, CXCL12) and its receptor CXCR4 was investigated in 56 primary NPC biopsy specimens from Chinese NPC patients in parallels with LMP1 antigen and EBER1 by immunohistochemisty (IHC) and in situ hybridization (ISH). Moreover, the expression levels of HLA class I (b-microglobulin) and II antigen (HLA-DR), and co-stimulatory molecule CD54 were also evaluated in 31 out of these 56 patients using immunohistochemisty (IHC). Our results showed that (a) the elevated expression levels of IP10, SDF-1, CXCR4, b-microglobulin, HLA-DR and CD54 in NPC lesions was 66%, 36%, 30%, 42%, 55% and 69%, respectively. (b) High expression of SDF-1 was observed in advanced NPC (N stage, p < 0.05). (c) LMP1 expression correlated with upregulation of CXCR4 and translocation of CXCR4 to the nucleus of the tumor cells. This role of LMP1 in regulating the expression of CXCR4 was confirmed in the EBV positive NPC cell line C666 by inhibition of LMP1 expression with small interfering RNA (siRNA). Our findings provide new insights on the immune status of the malignant cells which may affect the outcome of immunotherapy in NPC. The differentiated nonkeratinizing and undifferentiated types of nasopharyngeal carcinoma (NPC) are associated with Epstein-Barr virus (EBV) in South China, which has the highest incidence rate in the world. The EBV latent type II antigens include nuclear antigen 1 (EBNA1), and latent membrane protein 1 (LMP1, in approximately 50%, seen in ref. 2) and protein 2 (LMP2), in addition small non-polyadenylated viral RNAs non-coding nuclear RNAs (EBERs) and BamHI-A rightward transcripts (BARTs) expressed in NPC tumor cells. The expressions of EBV antigens in NPC tumor cells provide the targets for adoptive immunotherapy. However, the poorly differentiated NPC is always characterized by the presence of a highly cellular lymphoid stroma admixed with tumor cells. However, the role of local immunity surrounding NPC cells and the role EBV and viral products expressed in tumor cell remain unclear, which is associated with the expression of immune-related molecules including chemokines and receptors, HLA class I and II antigens, and co-stimulatory molecules and the role of EBV and viral products to alter the expression of immune-related molecules on tumor cells. It has been reported that the expression pattern of immune related-molecules on tumor cells will affect the outcome of T-cell-based adoptive immunotherapy for NPC.
Li
Jiang
J
State Key Laboratory of Oncology in South China, Sun Yat-sen University, Cancer Center, Guangzhou, China.
Zhang
Xiao-Shi
XS
Xie
Dan
D
Deng
Hai-Xia
HX
Gao
Yan-Fang
YF
Chen
Qiu-Yan
QY
Huang
Wen-Lin
WL
Masucci
Maria G
MG
Zeng
Yi-xin
YX
D021581:Active Transport, Cell Nucleus / Q000502:physiology; D000328:Adult; D000368:Aged; D002277:Carcinoma / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D054357:Chemokine CXCL10 / Q000096:biosynthesis / Q000235:genetics; D054377:Chemokine CXCL12 / Q000096:biosynthesis / Q000235:genetics; D002681:China; D020031:Epstein-Barr Virus Infections / Q000276:immunology / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D015967:Gene Expression Regulation, Viral; D006680:HLA Antigens / Q000096:biosynthesis / Q000235:genetics; D004854:Herpesvirus 4, Human / Q000502:physiology*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009303:Nasopharyngeal Neoplasms / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism; D014763:Viral Matrix Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D001613:beta 2-Microglobulin / Q000096:biosynthesis / Q000235:genetics
C114753:CXCL10 protein, human; C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054357:Chemokine CXCL10; D054377:Chemokine CXCL12; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D006680:HLA Antigens; D009363:Neoplasm Proteins; D019718:Receptors, CXCR4; D014763:Viral Matrix Proteins; D001613:beta 2-Microglobulin; D018799:Intercellular Adhesion Molecule-1