Transcriptional Upregulation of NLRC5 by Radiation Drives STING- and Interferon-Independent MHC-I Expression on Cancer Cells and T Cell Cytotoxicity

Abstract

Radiation therapy has been shown to enhance the efficacy of various T cell-targeted immunotherapies that improve antigen-specific T cell expansion, T regulatory cell depletion, or effector T cell function. Additionally, radiation therapy has been proposed as a means to recruit T cells to the treatment site and modulate cancer cells as effector T cell targets. The significance of these features remains unclear. We set out to determine, in checkpoint inhibitor resistant models, which components of radiation are primarily responsible for overcoming this resistance. In order to model the vaccination effect of radiation, we used a Listeria monocytogenes based vaccine to generate a large population of tumor antigen specific T cells but found that the presence of cells with cytotoxic capacity was unable to replicate the efficacy of radiation with combination checkpoint blockade. Instead, we demonstrated that a major role of radiation was to increase the susceptibility of surviving cancer cells to CD8+ T cell-mediated control through enhanced MHC-I expression. We observed a novel mechanism of genetic induction of MHC-I in cancer cells through upregulation of the MHC-I transactivator NLRC5. These data support the critical role of local modulation of tumors by radiation to improve tumor control with combination immunotherapy.

MHC class I transactivator NLRC5 in host immunity, cancer and beyond

“…Enhanced expression of MHC class I and antigen presentation genes in mouse melanoma cells through stable transfection of NLRC5 dramatically inhibited in vivo tumor growth and metastatic lung foci formation 55 . Similarly, irradiation‐induced up‐regulation of NLRC5 gene expression has been shown as a key component of CD8 + T‐cell‐mediated killing of cancer cells during radiotherapy in a murine pancreatic adenocarcinoma model 56 . In line with these findings, retrospective analysis of patients (7747 samples) from The Cancer Genome Atlas database revealed NLRC5 to be an important regulator of the MHC class I pathway in human cancer 57 .…”

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

“…NLRC5 gene transcription is also inhibited by protein arginine methyltransferase 5 (PRMT5) which catalyzes methylation of arginine residues on several histones (H2AR3, H3R2, H3R8 and H4R3) [ 181 , 182 ]. Modulation of the epigenetic signature at the NLRC5 promoter is also implicated in STAT1-independent upregulation of NLRC5 and MHC-I genes in pancreatic cancer cells exposed to ionizing radiation, although an earlier report attributed radiation-induced MHC-I upregulation in breast cancer cell lines to secretion of IFNβ [ 183 , 184 ]. Increased CpG methylation of the NLRC5 and other IFN-I-responsive genes was reported in the genomic DNA of systemic lupus erythematosus patients that correlated with increased auto-antibody production, suggesting that epigenetic modulation of NLRC5 may also be influenced by systemic inflammation [ 185 ].Moreover, the chicken NLRC5 gene was reported to harbor two CpG islands, one near the proximal core promoter that is unmethylated, and the second one encompassing an additional STAT1 binding site (distal to the STAT1-NF-κB site) that could be methylated [ 186 ].…”

Tackling Resistance to Cancer Immunotherapy: What Do We Know?

“…Radiation therapy was also able to increase the recognition of tumor cells by the immune system through upregulation of MHC Class I molecules in tumor cells [ 76 , 77 , 85 , 86 ]. Induction of MHC Class I expression after radiation therapy was related with IFN-1, in particular, IFN-β secretion by tumor cells themselves [ 86 ].…”

“…However, the upregulation of MHC Class I after radiation could also occur without IFN-β. Radiation has been proven to increase the expression of NLRC5 [ 85 ], an MHC class I transactivator, as discussed above. The induction of NLRC5 following radiation induced MHC class I expression independent of IFN-β [ 85 ].…”

“…Radiation has been proven to increase the expression of NLRC5 [ 85 ], an MHC class I transactivator, as discussed above. The induction of NLRC5 following radiation induced MHC class I expression independent of IFN-β [ 85 ]. The higher MHC Class I expression will later lead to improved tumor recognition through enhanced antigen presentation.…”