Galectin 9 and PINCH, novel immunotherapy targets of renal cell carcinoma: a rationale to find potential tumour antigens and the resulting cytotoxic T lymphocytes induced by the derived peptides.

ABSTRACT

OBJECTIVE: To analyse and then generalize the mechanism by which partial or complete response is achieved among a limited number of patients with metastatic renal cell carcinoma (RCC) treated with interferon or interleukin-2. MATERIALS AND METHODS: An expression library of RCC (clear-cell carcinoma) was screened using the sera of patients with metastatic RCC who benefited from partial or complete response to cytokine therapy, the postulation being that those remarkable responders obtained specific cellular immunity against RCC with the antibodies to react with the cancer antigen. Peripheral blood mononuclear-cells (PBMCs) from healthy volunteers were stimulated with the antigen-derived peptides to induce specific cytotoxic T lymphocytes (CTLs). Specific activities of CTLs were measured by 5¹Cr-releasing assay. RESULTS: Among 15 positive clones isolated, two novel genes, galectin 9 and PINCH, were expressed at much higher levels in cancerous lesions than in normal tissues in all the patients with clear-cell carcinoma who were examined. Both HLA-A*2402-restricted and HLA-A*0201-restricted CTLs were induced by each antigen-derived peptide to exhibit specific and highly cytotoxic activities towards RCC cells. Specific CTLs were induced abundantly, as shown by flow cytometry analysis of the CTLs labelled with fluorescein isothiocyanate anti-CD107a and APC anti-CD8. The clonal expansion of the CTLs was shown by the clonality of T-cell receptor Vß repertoires. CONCLUSION: A novel approach based on clinical observations yielded promising tumour antigens as immunotherapy targets of RCC.