The MHC Class-I Transactivator NLRC5: Implications to Cancer Immunology and Potential Applications to Cancer Immunotherapy

Abstract

The immune system constantly monitors the emergence of cancerous cells and eliminates them. CD8+ cytotoxic T lymphocytes (CTLs), which kill tumor cells and provide antitumor immunity, select their targets by recognizing tumor antigenic peptides presented by MHC class-I (MHC-I) molecules. Cancer cells circumvent immune surveillance using diverse strategies. A key mechanism of cancer immune evasion is downregulation of MHC-I and key proteins of the antigen processing and presentation machinery (APM). Even though impaired MHC-I expression in cancers is well-known, reversing the MHC-I defects remains the least advanced area of tumor immunology. The discoveries that NLRC5 is the key transcriptional activator of MHC-I and APM genes, and genetic lesions and epigenetic modifications of NLRC5 are the most common cause of MHC-I defects in cancers, have raised the hopes for restoring MHC-I expression. Here, we provide an overview of cancer immunity mediated by CD8+ T cells and the functions of NLRC5 in MHC-I antigen presentation pathways. We describe the impressive advances made in understanding the regulation of NLRC5 expression, the data supporting the antitumor functions of NLRC5 and a few reports that argue for a pro-tumorigenic role. Finally, we explore the possible avenues of exploiting NLRC5 for cancer immunotherapy.

MHC Class I Deficiency in Solid Tumors and Therapeutic Strategies to Overcome It

“…Alterations in NLRC5 expression in cancer. IFNγ stimulates MHC-I expression in cancer through multiple ways, of which the induction of NLRC5 expression followed by the formation of CITA enhanceosome (Figure 1) is the principal mechanism of IFNγ-induced increase in MHC-I (reviewed in [83]). Four independently generated Nlcr5-deficient mouse strains demonstrated the principal role of NLRC5 in the regulation of both classical and non-classical MHC-I genes and APM components [84][85][86][87].…”

“…Transcriptional downregulation of MHC-I expression is commonly observed in cancer and it is accompanied by reduced expression of the APM components, as the two are strongly correlated [15,97,98]. MHC-I downregulation in cancer is driven by several mechanisms, including (i) reduced IFNγ production by tumor-specific T cells due to tumor antigen loss (such as the result of de-differentiation) and/or T-cell functional inactivation through the expression of multiple inhibitory checkpoints [58,99], (ii) alterations in IFNγ signaling in cancer cells, including both loss of responsiveness via inactivation of IFNγ signaling pathways and sustained intrinsic IFNγ signaling [46,74,76,99]; (iii) alterations in NLRC5 expression in cancer cells [83]; (iv) epigenetic regulation of MHC-I expression, through DNA hypermethylation, histone deacetylation and trimethylation of H3K27 [43,44,100] (Figure 1). These mechanisms often overlap in emerging tumor subclones, driving intraand inter-lesional heterogeneity, clonal evolution and treatment resistance [93,101,102].…”

Open MHC Class I Conformers: A Look through the Looking Glass

“…Thus, chronic inflammation is characterized by high levels of IFN-β, IFN-γ, and TNF-α [ 79 , 80 ]. These cytokines use signaling pathways that enhance MHC-I gene transcription and induce an increase in the expression of closed and open MHC-I conformers at the plasma membrane of a variety of cell types, including tumor cells [ 81 , 82 , 83 , 84 ]. Therefore, within an inflammatory context, such as during malignant transformation, the expression of open conformers and αHC homodimers is a likely outcome.…”

Optimizing NK Cell-Based Immunotherapy in Myeloid Leukemia: Abrogating an Immunosuppressive Microenvironment

“…In tumor cells, downregulation of MHC-I ligands of inhibitory receptors results in the loss of inhibitory signaling and in a "missing-self" NK cell activation. Downregulation of MHC-I and key proteins of the antigen processing and presentation machinery (APM) is a key mechanism of cancer immune evasion (244). Cancer cells can reduce the HLA class I expression under the pressure of T cell surveillance (i.e., to escape T cell response).…”