Favorable prognosis of renal cell carcinoma with increased expression of chemokines associated with a Th1‐type immune response

• Published in: Cancer science 2006-08, Vol.97 (8), p.780-786
• Main Authors: Kondo, Tsunenori, Nakazawa, Hayakazu, Ito, Fumio, Hashimoto, Yasunobu, Osaka, Yukinari, Futatsuyama, Kazuya, Toma, Hiroshi, Tanabe, Kazunari
• Format: Article
• Language: English
• Subjects: Aged; Biological and medical sciences; Carcinoma, Renal Cell - diagnosis; Carcinoma, Renal Cell - genetics; Carcinoma, Renal Cell - immunology; Chemokine CXCL10; Chemokine CXCL11; Chemokine CXCL9; Chemokines - genetics; Chemokines, CXC - genetics; Cytokines - genetics; Female; Gene Expression; Humans; Interferon-gamma - genetics; Kidney Neoplasms - diagnosis; Kidney Neoplasms - genetics; Kidney Neoplasms - immunology; Kidneys; Male; Medical sciences; Middle Aged; Nephrology. Urinary tract diseases; Original; Prognosis; Receptors, Chemokine - analysis; Receptors, CXCR3; Receptors, CXCR5; Receptors, Cytokine - analysis; RNA, Messenger - analysis; RNA, Messenger - metabolism; Th1 Cells - chemistry; Th1 Cells - immunology; Th2 Cells - chemistry; Th2 Cells - immunology; Tumors; Tumors of the urinary system
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/j.1349-7006.2006.00231.x

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‐γ 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)‐γ (MIG) expression was an independent favorable prognostic factor. Immunohistochemistry showed that the degree of CXCR3‐positive cell infiltration significantly correlated with IFN‐γ inducible protein 10, MIG and IFN‐γ‐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. (Cancer Sci 2006; 97: 780–786)