Correlation between expression of cyclooxygenase-2 and the presence of CD4+ infiltrating T-lymphocyte in human primary hepatocellular carcinoma.
OBJECTIVE
Recent studies have found that Cyclooxygenase-2(Cox-2) is frequently inappropriately expressed in primary hepatocellular carcinoma (HCC), suggesting that abnormal Cox-2 expression plays an important role in hepatocarcinogenesis. But it remains controversial in these reports. Moreover, there are only a few studies on the correlation between Cox-2 and infiltrating immunocytes in the tumor-microenvironment. CD4+ tumor-infiltrating lymphocytes (TIL) and infiltrating immunocytes around the tumor are closely correlated to the development of the tumor, but so far no reports are available showing the relationship among Cox-2, CD4+ TIL of tumor and CD4+ infiltrating T-lymphocytes of adjoining non-tumorous (ANT) tissues in tumor-microenvironment. This study is designed to appropriately select and collect patients' specimens to better reflect Cox-2 expression in human HCC, and also to stress the correlation among Cox-2, CD4+ TIL and CD4+ infiltrating T-lymphocytes in the tumor-microenvironment.


METHODS
Tumor tissue, and its matched ANT tissue removed less than 1 cm from the solid tumor border, were obtained from 25 HCC patients all of whom came from Hunan province, China, and were infected with hepatitis B virus (HBV). Normal liver tissues of 10 hemangiomas were collected as controls. Both Cox-2 expression and the number of CD4+ TIL and CD4+ infiltrating T-lymphocyte were detected by immunohistochemistry, and data were analyzed closely with patients' clinical figures so as to investigate the correlation between the 3 elements.


RESULTS
In 25 HCC patients, remarkably higher Cox-2 expression in both tumor and ANT tissues was observed compared with normal liver tissues (p < 0.001). The percentage of Cox-2 positive cells was, remarkably, higher in ANT tissues than in tumors (p < 0.001). Similarly the distribution of CD4+ T cells was significantly higher in ANT tissue than in tumor tissue (p < 0.0001), and also significantly higher in tumor tissue than in normal tissue (p < 0.0001). Importantly, in the group of patients with Cox-2-expressing tumors, the number of CD4+ infiltrating T-lymphocyte in ANT tissues was 79.4(+)9.92/hpf, which is obviously lower (p = 0.019) than that of the group with non-Cox-2-expressing tumors with the number of CD4+ infiltrating T-lymphocyte in ANT tissues at 118.13(+)12.47/hpf. Cox-2 expression of tumors showed a significant negative correlation with number of CD4+ infiltrating T cells of ANT tissues (r = 0.499, p = 0.024). The number of CD4+ TILs are lower in Cox-2-expressing tumors than in non-Cox-2-expressing tumors, but there was not statistical significance (p = 0.057).


CONCLUSIONS
Taken together we suggest in the tumor-microenvironment of HCC the expression of Cox-2 may inhibit the number CD4+ infiltrating T-lymphocyte in ANT tissues. As a result, Cox-2 overexpression may contribute to both suppression of local immune responses and enhancement of metastatic potential in human HCC.
Gao
Ya-Wei
YW
Department of Immunology, Xiangya School of Medicine, Central South University, Changsha, PR China.
Chen
Yu-Xiao
YX
Wang
Zhi-Ming
ZM
Zhou
Le-Du
LD
Li
Xin-Ying
XY
Li
Li-Xin
LX
Luo
Qi-Zhi
QZ
Tian
Wei
W
Fu
Chun-Yan
CY
Zhou
Jian-Hua
JH
D000328:Adult; D000368:Aged; D015704:CD4 Antigens; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology*; D051546:Cyclooxygenase 2 / Q000096:biosynthesis*; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D013601:T-Lymphocytes / Q000276:immunology*
D015704:CD4 Antigens; D051546:Cyclooxygenase 2