NLRC5-CIITA Fusion Protein as an Effective Inducer of MHC-I Expression and Antitumor Immunity

Abstract

Aggressive tumors evade cytotoxic T lymphocytes by suppressing MHC class-I (MHC-I) expression that also compromises tumor responsiveness to immunotherapy. MHC-I defects strongly correlate to defective expression of NLRC5, the transcriptional activator of MHC-I and antigen processing genes. In poorly immunogenic B16 melanoma cells, restoring NLRC5 expression induces MHC-I and elicits antitumor immunity, raising the possibility of using NLRC5 for tumor immunotherapy. As the clinical application of NLRC5 is constrained by its large size, we examined whether a smaller NLRC5-CIITA fusion protein, dubbed NLRC5-superactivator (NLRC5-SA) as it retains the ability to induce MHC-I, could be used for tumor growth control. We show that stable NLRC5-SA expression in mouse and human cancer cells upregulates MHC-I expression. B16 melanoma and EL4 lymphoma tumors expressing NLRC5-SA are controlled as efficiently as those expressing full-length NLRC5 (NLRC5-FL). Comparison of MHC-I-associated peptides (MAPs) eluted from EL4 cells expressing NLRC5-FL or NLRC5-SA and analyzed by mass spectrometry revealed that both NLRC5 constructs expanded the MAP repertoire, which showed considerable overlap but also included a substantial proportion of distinct peptides. Thus, we propose that NLRC5-SA, with its ability to increase tumor immunogenicity and promote tumor growth control, could overcome the limitations of NLRC5-FL for translational immunotherapy applications.

NLRC5 overexpression in ovarian tumors remodels the tumor microenvironment and increases T-cell reactivity toward autologous tumor-associated antigens

“…Santharam et al. ( 67 ) similarly found that EL-4 lymphoma cells overexpressing NLRC5 increase the production and repertoire of MHC-I-associated peptides. These observations align with our findings showing an increased antitumoral response to an infected cell vaccine overexpressing NLRC5.…”

Response to "NLRC5germline variants and their potential role in eliciting an immune response in patients with cancer treated with immune checkpoint inhibitors" by Xiang-Yu Meng

“…Regarding the potential of NLRC5 as a predictive biomarker of tumor response to ICIs, there are emerging reports connecting NLRC5 to treatment response for various cancers, 3 4 with multiple studies suggesting that the mechanism is based on tumor evasion and mediated by human leukocyte antigens (HLA) expression. 5 Additionally, the correlation between irAEs and favorable response to ICIs has been widely demonstrated, and Jiang et al recently suggested that HLA alterations are the link between the two.…”