Retinoids as critical modulators of immune functions: new therapeutic perspectives for old compounds

Retinoids are vitamin A derivatives that critically regulate several physiological and pathological processes, including immune functions and cancer development. These biological response modifiers exert their pleiotropic effects through the interaction with nuclear receptors, defined as retinoic acid receptors (RARs) and retinoid X receptors (RXRs). These ligand-activated nuclear receptors induce the transcription of target genes by binding to responsive elements in the promoter regions. RARs and RXRs are also capable to interact with other nuclear receptors, thus expanding their spectrum of action on gene expression. Evidence has been accumulated indicating that retinoids may exert beneficial effects in both immune-mediated disorders and tumors. With regard to cancer, retinoids directly target neoplastic cells by inducing differentiation, inhibiting cell growth or promoting survival. However, the efficacy of these compounds in cancer treatment probably resides in their ability to modulate also the function of immune effectors. Vitamin A derivatives are currently used in the therapy of acute promyelocytic leukemia and of cutaneous T cell lymphomas, but they could be effective also on B-cell malignancies. Clinical trials are ongoing to test their efficacy in solid tumors. In this review, we give a broad depiction of how retinoids influence the function of immune effectors and affect growth and survival of hematological malignancies. This with the aim to better understand the clinical effects of retinoid-based therapies and provide the rationale to combine retinoids with other active compounds in new synergistic treatment strategies.