miR‐148a‐3p silences the CANX/MHC‐I pathway and impairs CD8⁺T cell‐mediated immune attack in colorectal cancer

Abstract

Nonresponse, or acquired resistance to immune checkpoint inhibitors in colorectal cancer (CRC) highlight the importance of finding potential tolerance mechanisms. Low expression of major histocompatibility complex, class I (MHC-I) on the cell surface of the tumor is one of the main mechanisms of tumor escape from T-cell recognition and destruction. In this study, we demonstrated that a high level of calnexin (CANX) in the tumors is positively correlated with the overall survival in colorectal cancer patients. CANX is a chaperone protein involved in the folding and assembly of MHC-I molecules. Using miRNA target prediction databases and luciferase assays, we identified miR-148a-3p as a potential regulator of CANX. Inhibition of miR-148a-3p restores surface levels of MHC-I and significantly enhanced the effects 2 of 16 | ZHENG Et al.Proteins were extracted from whole cells and then characterized by western blot analysis. Cells were pelleted and then lysed in radioimmunoprecipitation assay buffer. Cells were of CD8 + T-cell-mediated immune attack in vitro and in vivo by promoting CANX expression. These results reveal that miR-148a-3p can function as a tumor promotor in CRC by targeting the CANX/MHC-I axis, which provides a rationale for immunotherapy through targeting the miR-148a-3p/CANX/MHC-I pathway in patients with CRC.

A Novel Defined Necroptosis-Related miRNAs Signature for Predicting the Prognosis of Colon Cancer

“…36 In colorectal cancer, the inhibition of tumor promoter miR-148a-3p can restore the surface level of MHC-I and significantly enhance the effect of CD8+ T cell-mediated immune attack by promoting the expression of calnexin. 37 However, a study reported that the low expression of miR-148a is associated with the significant reduction of disease-free survival and overall survival, 38 indicating that the mechanism between miR-148a-3p and colorectal cancer is not precise. 39 By analyzing accessible online databases, we argued the potential target genes and functions of the above three miRNAs.…”

Metabolomics of Acute vs. Chronic Spinach Intake in an Apc–Mutant Genetic Background: Linoleate and Butanoate Metabolites Targeting HDAC Activity and IFN–γ Signaling

“…Notably, increased cell surface occupancy of β2m was confirmed in FACS-based analyses, and the functionality of MHC-I complexes was corroborated in MC38-OVA+B3Z co-culture experiments. Downregulation of MHC-I components is a potential oncogenic driver [29][30][31][32][33], and the targeting of epigenetic 'readers', 'writers' and 'erasers' might facilitate re-expression of cell surface MHC complexes to reengage host immune pathways in cancer cells. These mechanisms also might be pertinent at earlier stages, as in the case of adenomatous colon tumors from the Pirc model and in FAP or Lynch Syndrome patients, which harbor predicted MHC neoantigens [42].…”

“…No corresponding changes were noted for Nlrc5, a master transcriptional regulator of MHC-I signaling [29], or endoplasmic reticulum transporters such as Tap1. Calnexin (Canx), a chaperone protein involved in the folding of MHC-I molecules [33], was markedly downregulated in Pirc colon tumors, and chronic SPI intake partially reversed this trend (Figure 8A, dashed red box)-although not to the levels observed in WT normal AIN controls. Compared to Pirc tumor AIN and Pirc tumor SPI3d groups, Pirc tumor SPI samples had reduced Foxp3, Iκbα, and Survivin expression (Figure 8A).…”

Non-Coding RNAs Regulate the Resistance to Anti-EGFR Therapy in Colorectal Cancer

“…For instance, a recent study has shown miR-34a promoted the expression of B7-H3 and TNF-a in tumor microenvironment and negatively regulated T cell-mediated immune response, which thus induced immunosuppression and immune escape in CRC (66). MiR-148a-3p and miR-448 respectively down-regulate the expression of calnexin (CANX) and indoleamine 2,3-dioxygenase 1 (IDO1), which enhances CD8 + T cell-mediated immune response in CRC (67,68). Cetuximab can induce ADCC by binding to EGFR on cancer cells and CD16 receptor on natural killer (NK) cells and dendritic cells (DCs) (69)(70)(71).…”