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 Vβ repertoires. Conclusion• A novel approach based on clinical observations yielded promising tumour antigens as immunotherapy targets of RCC.

Galectin Targeted Therapy in Oncology: Current Knowledge and Perspectives

“…High Gal-9 expression is associated with decreased overall survival (OS) time and decreased recurrence free survival (RFS). Patients with high Gal-9 expression showed more advanced progression of the disease with larger tumor size and necrosis [ 168 ]. Interestingly, Gal-9 proved ineffective in the stratification of patients with advanced disease (TNM III/IV, Fuhrman 3/4).…”

Present and future perspectives on immunotherapy for advanced renal cell carcinoma: Going to the core or beating around the bush?

“…We identified two novel genes, galectin 9 and PINCH, as RCC-specific antigens that were specifically highly expressed in all the tested clear cell carcinoma samples, compared with normal renal tissues (21). Using peptides derived from these two antigens, we induced HLA-A*2402-restricted CTL clones and HLA-A*0201-restricted CTLs with high antigen-specific killing activities toward RCC cells (21) (Figure 1) . These antigens seemed to be closely related to an immune escape mechanism, cancer cell survival, and metastases of RCC.…”

“…The abilities of the identified antigens to induce CTLs with specific, high cytotoxicity was then evaluated. This method involved basic molecular cloning techniques using clinical samples, and was developed by a urologist with extensive experience, including many clinical cases of RCC (21). …”

Combination immunotherapy with interleukin‐2 surface‐modified tumor cell vaccine and programmed death receptor‐1 blockade against renal cell carcinoma

“…At present, therapeutic vaccines have been extensively used to generate endogenous tumor‐reactive T cells for cancer treatment . As a result of the weak immunogenicity of tumor cells, cytokines with immunopotentiating effects are widely used for immunotherapy of tumors .…”