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.
Highlights
The concept of natural anti-cancer immunity faced decades of skepticism before receiving formal acceptance with the recognition of ‘cancer immune evasion’ as one of the hallmarks of cancer in the updated treatise of Hanahan and Weinberg [1,2]
This study showed that NLRC5 is strongly induced by IFNγ and that NLRC5 targeting siRNA attenuated IFNγ-mediated upregulation of MHC class-I (MHC-I), indicating that NLRC5 is a crucial mediator of IFNγ-stimulated upregulation of the MHC-I antigen presentation pathway
In an effort to elucidate the mechanisms underlying this regulation, the Cui group showed that TLR4 stimulation activates the TRAF2/6 complex, which ubiquitinates NLRC5 on Lys1178 residue, presumably leading to its degradation and release of IKKα and IKKβ to complex with IKKγ [204,205] (Figure 3) This study showed that the ubiquitin-specific protease 14 (USP14) deubiquitinates NLRC5 to sustain the NLRC5-mediated inhibition of NF-κB activation
Summary
The concept of natural anti-cancer immunity faced decades of skepticism before receiving formal acceptance with the recognition of ‘cancer immune evasion’ as one of the hallmarks of cancer in the updated treatise of Hanahan and Weinberg [1,2]. Current cancer immunotherapy approaches are predominantly aimed at (i) stimulating anti-cancer T cells (through identification of tumor antigens for personalized vaccines, (ii) inducing immunogenic cell death of tumors (chemotherapeutic agents, killing by oncolytic virus), (iii) achieving efficient activation of antitumor T lymphocytes (via blocking checkpoints, inhibiting immune suppressive cells) and (iv) introducing tumor-reactive CTLs (antitumor CTLs expanded in vitro, engineered CAR-T cells targeting specific tumor antigens), either individually or in different combinations. We briefly discuss cancer antigens, the antigen processing pathway that generates MHC-I binding peptides and the various defects of this pathway before describing in detail the biology of NLRC5, its implications in cancer immunogenicity and potential ways of exploiting NLRC5 to restore MHC-I expression in order to elicit antitumor immunity [26,27,28]
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