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Clinical Cancer Research Vol. 8, 2690-2695, August 2002
© 2002 American Association for Cancer Research

Experimental Therapeutics, Preclinical Pharmacology

5-aza-2'-Deoxycytidine-induced Expression of Functional Cancer Testis Antigens in Human Renal Cell Carcinoma

Immunotherapeutic Implications1

Sandra Coral, Luca Sigalotti, Maresa Altomonte, Arne Engelsberg, Francesca Colizzi, Ilaria Cattarossi, Eugene Maraskovsky, Elke Jager, Barbara Seliger and Michele Maio2

Cancer Bioimmunotherapy Unit, Centro di Riferimento Oncologico, Istituto di Ricovero e Cura a Carattere Scientifico, 33081 Aviano, Italy [S. C., L. S., M. A., F. C., I. C., M. M.]; Johannes Gutenberg University, III. Department of Internal Medicine, 55131 Mainz, Germany [A. E., B. S.]; Ludwig Institute for Cancer Research, Austin and Repatriation Medical Centre, Heidelberg, Victoria 3084, Australia [E. M.]; and Nordwest Krankenhaus, Department of Internal Medicine, 60488 Frankfurt, Germany [E. J.]

Purpose: Limited therapeutic options are presently available for advanced renal cell carcinoma (RCC). This study was designed to define the clinical potential of the DNA hypomethylating agent 5-aza-2'-deoxycytidine (5-AZA-CdR) in human RCC, through its control of the expression of "therapeutic targets" of the cancer testis antigen (CTA) family, and of the tumor-associated antigen RAGE-1, in RCC cells.

Experimental Design: Reverse transcription (RT)-PCR assays of a panel of RCC cells treated with 5-AZA-CdR, investigated the induction of the expression of several CTAs and of RAGE-1. Immunoprecipitation and Western blotting assessed whether the expression of CTA-specific mRNA induced by 5-AZA-CdR resulted in a translated protein of appropriate molecular weight. The functional activity of de novo expressed CTA was evaluated using 51Cr release cytotoxicity assays of 5-AZA-CdR-treated HLA-A2-positive RCC cells using HLA-A2-restricted NY-ESO-1-specific CTLs.

Results: Exposure to 5-AZA-CdR invariably induced the expression of the CTA MAGE-1, -2, -3, and -4, GAGE 1-6, and NY-ESO-1 in all of the RCC cells investigated. De novo expression of NY-ESO-1 was persistent, being still detectable 60 days after the end of treatment, and generated a functional protein efficiently recognized by HLA-A2-restricted NY-ESO-1-specific CTLs. 5-AZA-CdR also induced RAGE-1 expression in RAGE-1-negative RCC and sarcoma cells but not in neoplastic cells of different histology.

Conclusions: This study provides the scientific rationale to establish new strategies of chemoimmunotherapy in RCC patients. The well-defined immunogenicity of the investigated CTAs and of RAGE-1 suggest that systemic administration of 5-AZA-CdR represents a promising strategy to enhance the constitutively poor immunogenic potential of RCC cells, and to propose that virtually all RCC patients receive active and/or adoptive CTA- or RAGE-1-based immunotherapy.




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