| RRC ID |
78093
|
| Author |
Sun X, Watanabe T, Oda Y, Shen W, Ahmad A, Ouda R, de Figueiredo P, Kitamura H, Tanaka S, Kobayashi KS.
|
| Title |
Targeted demethylation and activation of NLRC5 augment cancer immunogenicity through MHC class I.
|
| Journal |
Proc Natl Acad Sci U S A
|
| Abstract |
Impaired expression of MHC (major histocompatibility complex) class I in cancers constitutes a major mechanism of immune evasion. It has been well documented that the low level of MHC class I is associated with poor prognosis and resistance to checkpoint blockade therapies. However, there is lmited approaches to specifically induce MHC class I to date. Here, we show an approach for robust and specific induction of MHC class I by targeting an MHC class I transactivator (CITA)/NLRC5, using a CRISPR/Cas9-based gene-specific system, designated TRED-I (Targeted reactivation and demethylation for MHC-I). The TRED-I system specifically recruits a demethylating enzyme and transcriptional activators on the NLRC5 promoter, driving increased MHC class I antigen presentation and accelerated CD8+ T cell activation. Introduction of the TRED-I system in an animal cancer model exhibited tumor-suppressive effects accompanied with increased infiltration and activation of CD8+ T cells. Moreover, this approach boosted the efficacy of checkpoint blockade therapy using anti-PD1 (programmed cell death protein) antibody. Therefore, targeting NLRC5 by this strategy provides an attractive therapeutic approach for cancer.
|
| Volume |
121(6)
|
| Pages |
e2310821121
|
| Published |
2024-2-6
|
| DOI |
10.1073/pnas.2310821121
|
| PMID |
38300873
|
| MeSH |
Animals
Demethylation
Genes, MHC Class I* / genetics
Histocompatibility Antigens Class I
Neoplasms* / genetics
Trans-Activators / metabolism
|
| Resource |
| Human and Animal Cells |
B16F10(RCB2630)
MCF7(RCB1904) |
