5-aza-2′-deoxycytidine-induced expression of functional cancer testis antigens in human renal cell carcinoma: Immunotherapeutic implications

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

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)2690-2695
Number of pages6
JournalClinical Cancer Research
Volume8
Issue number8
Publication statusPublished - 2002

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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    Coral, S., Sigalotti, L., Altomonte, M., Engelsberg, A., Colizzi, F., Cattarossi, I., Maraskovsky, E., Jager, E., Seliger, B., & Maio, M. (2002). 5-aza-2′-deoxycytidine-induced expression of functional cancer testis antigens in human renal cell carcinoma: Immunotherapeutic implications. Clinical Cancer Research, 8(8), 2690-2695.