The MHC class II transactivator CIITA induction as a potential new tool to develop anti-tumor vaccines and predict the efficacy of immunotherapy.

The MHC class II transactivator (CIITA) is the master regulator of MHC class II (MHC-II) genes expression. In fact, it promotes both constitutive and interferon gamma-inducible expression of all MHC-II genes and thus regulates the optimal activation of adaptive immunity, which depends on the proper activation of CD4+ T helper cells. In this review we will briefly discuss the role and regulation of CIITA and the downstream expression of MHC-II in adaptive immunity, followed by a discussion of how the induction of CIITA and MHC-II expression in tumor cells of different histological origins can make them surrogate antigen presenting cells for their own tumor antigens, thereby enabling them to elicit a protective adaptive anti-tumor immune response. Based on this concept, we will discuss possible strategies to use CIITA-driven MHC-II-positive tumor cells to unveil tumor antigens and develop different types of anti-tumor vaccines, including CIITA-based vaccination strategies. We will also address the major challenges associated with in vivo CIITA delivery and critically discuss the apparently conflicting preclinical evidence obtained in glioblastoma models. Finally, we will highlight the potential of epigenetic drugs to directly induce CIITA-driven MHC-II-positive tumor cells capable of stimulating the immune system and discuss the potential of CIITA and MHC-II expression as predictive markers of response to immunotherapy, thereby providing a rationale for combining CIITA-inducing strategies with immune checkpoint inhibitors for future human clinical setting.