Favorable prognosis of renal cell carcinoma with increased expression of chemokines associated with a Th1-type immune response.
The potential role of chemokines in clinical tumors remains poorly understood. Recent investigations have shown the differential expression of chemokine receptors on lymphocytes mediating Th1- and Th2-type immune responses. We examined Th1- and Th2-associated cytokines and chemokines, as well as the expression of their receptors in tumor-infiltrating lymphocytes in renal cell carcinoma (RCC). Sixty-seven patients with sporadic RCC were analyzed for the expression of Th1- and Th2-associated genes using real-time polymerase chain reaction. Tumor infiltration by CXC chemokine receptor 3 (CXCR3)-positive and CC chemokine receptor 5 (CCR5)-positive cells was detected by immunohistochemistry and by flow cytometry. The expression of Th1-associated genes was significantly increased in tumors compared to normal kidney tissues. The expression of interferon-gamma correlated positively with that of Th1 chemokines. Tumors expressing higher Th1 chemokines did not recur after curative surgery. Multivariate analysis showed that increased monokine induced by interferon (IFN)-gamma (MIG) expression was an independent favorable prognostic factor. Immunohistochemistry showed that the degree of CXCR3-positive cell infiltration significantly correlated with IFN-gamma inducible protein 10, MIG and IFN-gamma-inducible T cell a chemoattractant expression (I-TAC). Flow cytometric analysis showed increased expression of CXCR3 and CCR5 in tumor-infiltrating T lymphocytes compared to that in peripheral blood T cells. These results suggest that upregulation of the Th1-type immune response in RCC tumors with a favorable prognosis may be mediated by Th1-associated chemokines. Integrity of the Th1-type immune response seems to be required for tumor regression, suggesting that detection and correction of a defect in the Th1-type response cascade would thus be one of the main targets for tailor-made immunotherapy and gene therapy in RCC.
Kondo
Tsunenori
T
Department of Urology, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan. tkondo@kc.twmu.ac.jp
Nakazawa
Hayakazu
H
Ito
Fumio
F
Hashimoto
Yasunobu
Y
Osaka
Yukinari
Y
Futatsuyama
Kazuya
K
Toma
Hiroshi
H
Tanabe
Kazunari
K
D000368:Aged; D002292:Carcinoma, Renal Cell / Q000175:diagnosis / Q000235:genetics / Q000276:immunology*; D054357:Chemokine CXCL10; D054371:Chemokine CXCL11; D054370:Chemokine CXCL9; D018925:Chemokines / Q000235:genetics*; D019743:Chemokines, CXC / Q000235:genetics; D016207:Cytokines / Q000235:genetics; D005260:Female; D015870:Gene Expression; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics; D007680:Kidney Neoplasms / Q000175:diagnosis / Q000235:genetics / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D054367:Receptors, CXCR3; D054380:Receptors, CXCR5; D019707:Receptors, Chemokine / Q000032:analysis; D018121:Receptors, Cytokine / Q000032:analysis; D018417:Th1 Cells / Q000737:chemistry / Q000276:immunology*; D018418:Th2 Cells / Q000737:chemistry / Q000276:immunology
C114753:CXCL10 protein, human; C515202:CXCL11 protein, human; C080810:CXCL9 protein, human; C515187:CXCR3 protein, human; C095085:CXCR5 protein, human; D054357:Chemokine CXCL10; D054371:Chemokine CXCL11; D054370:Chemokine CXCL9; D018925:Chemokines; D019743:Chemokines, CXC; D016207:Cytokines; D012333:RNA, Messenger; D054367:Receptors, CXCR3; D054380:Receptors, CXCR5; D019707:Receptors, Chemokine; D018121:Receptors, Cytokine; D007371:Interferon-gamma