The NLR member CIITA: Master controller of adaptive and intrinsic immunity and unexpected tool in cancer immunotherapy.

Human nucleotide-binding oligomerization domain (NOD)-like receptors (NLR) include a large family of proteins that have important functions in basic physio-pathological processes like inflammation, cell death and regulation of transcription of key molecules for the homeostasis of the immune system. They are all characterized by a common backbone structure (the STAND ATPase module consisting in a nucleotide-binding domain (NBD), an helical domain 1 (HD1) and a winged helix domain (WHD), used by both prokaryotes and eukaryotes as defense mechanism. In this review, we will focus on the MHC class II transactivator (CIITA), the master regulator of MHC class II (MHC-II) gene expression and the founding member of NLR. Although a consistent part of the described NLR family components is often recalled as innate or intrinsic immune sensors, CIITA in fact occupies a special place as a unique example of regulator of both intrinsic and adaptive immunity. The description of the discovery of CIITA and the genetic and molecular characterization of its expression will be followed by the most recent studies that have unveiled this dual role of CIITA, key molecule in intrinsic immunity as restriction factor for human retroviruses and precious tool to induce the expression of MHC-II molecules in cancer cells, rendering them potent surrogate antigen presenting cells (APC) for their own tumor antigens.

Protective anti-tumor vaccination against glioblastoma expressing the MHC class II transactivator CIITA.

Glioblastoma is the most malignant tumor of the central nervous system. Current treatments based on surgery, chemotherapy, and radiotherapy, and more recently on selected immunological approaches, unfortunately produce dismal outcomes, and less than 2% of patients survive after 5 years. Thus, there is an urgent need for new therapeutic strategies. Here, we report unprecedented positive results in terms of protection from glioblastoma growth in an animal experimental system after vaccination with glioblastoma GL261 cells stably expressing the MHC class II transactivator CIITA. Mice injected with GL261-CIITA express de novo MHC class II molecules and reject or strongly retard tumor growth as a consequence of rapid infiltration with CD4+ and CD8+ T cells. Importantly, mice vaccinated with GL261-CIITA cells by injection in the right brain hemisphere strongly reject parental GL261 tumors injected in the opposite brain hemisphere, indicating not only the acquisition of anti-tumor immune memory but also the capacity of immune T cells to migrate within the brain, overcoming the blood-brain barrier. GL261-CIITA cells are a potent anti-glioblastoma vaccine, stimulating a protective adaptive anti-tumor immune response in vivo as a consequence of CIITA-driven MHC class II expression and consequent acquisition of surrogate antigen-presenting function toward tumor-specific CD4+ Th cells. This unprecedented approach for glioblastoma demonstrates the feasibility of novel immunotherapeutic strategies for potential application in the clinical setting.