RARβ involvement in enhancement of lung tumor cell immunogenicity revealed by array analysis

The retinoid receptors (RARs and RXRs) ape mediators of the multiple effects of retinoic acid. Of these, the retinoic acid receptor beta 2 (RAR beta 2) has frequently been shown to be the principal mediator of the growth and tumor suppressive effects of retinoic acid; this gene is inactivated in many epithelial tumors and their derived cell lines. We have searched for genes that are regulated by this isoform and are potentially involved in tumor suppression. Using the Atlas human cDNA array I, we identified 27 genes (not counting RAR beta itself) that are regulated, directly or indirectly, by RAR beta 2 when it is transfected into Calu-1, a lung tumor-derived line that does not normally express RAR beta. Several of the affected genes code for proteins whose functions would augment the process of apoptosis and/or the host's immune response. The latter group included ICAM-1 and MHC class I heavy chain, whose protein products play particularly important roles in the mounting of an effective antitumor response. We then confirmed by flow cytometry that the observed increases in message levels were reflected in increased cell surface protein levels for ICAM-1 and MHC class I in RAR beta 2 transfectants of two RAR beta-deficient lines, Calu-1 and the epidermoid lung cancer-derived line SKMES. Finally, we showed that RAR beta 2 transfection of Calu-1 cells enhanced the heterologous CTL response in both the induction and the effector phases by up to threefold. These results support the hypothesis that down-regulation of these genes (and possibly others) in RAR beta-deficient tumor cells contributes to immune system evasion, and suggest a novel therapeutic approach for this disease.-Toulouse, A., Loubeau, M., Morin, Pappas, J. J., Wu, J., Bradley W. E. C. RAR beta involvement in enhancement of lung tumor cell immunogenicity revealed by array analysis.