RIG-I promotes immune evasion of colon cancer by modulating PD-L1 ubiquitination

Abstract

Colon cancer is one of the most prevalent cancers and exhibits high mortality worldwide. Despite the certain success in the immunotherapy of many tumor types, the limited response of colon cancer to immunotherapy remains a difficult problem. Retinoic acid-inducible gene-I (RIG-I) is a crucial component in innate antiviral immunity, but its role in antitumor immunity remains unclear. Here, in this report, we found that silencing RIG-I decreased resistance to tumor cells killed by T cells and attenuated colon tumor growth in immunocompetent mice. Meanwhile, overexpressing RIG-I promoted tumor progression, and high expression of RIG-I sensitized cells to anti-programmed cell death protein-1 (PD-1) therapy in vivo. Interestingly, we found that RIG-I influenced programmed cell death ligand 1 (PD-L1) expression to promote colon cancer immune evasion without relying on type I interferon stimulation. Mechanistically, RIG-I could compete with Speckle Type POZ protein (SPOP) to bind PD-L1, leading to attenuation of the polyubiquitination and proteasomal degradation of PD-L1. Collectively, our work reveals new insights into the contribution of RIG-I to driving immune evasion by maintaining the stability of PD-L1 through post-translational modification and provides a promising biomarker of the efficacy of immunotherapy in colon cancer.

Emerging therapeutic frontiers in cancer: insights into posttranslational modifications of PD-1/PD-L1 and regulatory pathways

“…Gao et al reported that Fusobacterium nucleatum , which is enriched in colorectal cancer tissues, upregulates the expression of PD-L1 by reducing the ubiquitination-mediated degradation of PD-L1 through IFIT1 [ 36 ]. RIG-I can compete with SPOP for binding to PD-L1, leading to reduced polyubiquitination and proteasome degradation of PD-L1 [ 37 ]. Ring finger protein 125 (RNF125) promotes ubiquitin-mediated degradation of PD-L1 and downregulates PD-L1 in oral squamous cell carcinoma (OSCC) TSCCA cells [ 38 ].…”

PTMs of PD-1/PD-L1 and PROTACs application for improving cancer immunotherapy

“…RIG-I modulated SPOP-mediated degradation of PD-L1 and elevated immune evasion in colon cancer ( 101 ). Suppressing RIG-I led to a decrease in the ability of T cells to eliminate tumor cells and reduced the growth of colon tumors in mice with a fully functional immune system.…”

“…Intriguingly, RIG-I modulates the expression of PD-L1, facilitating immune escape in colon cancer independently of type I interferon activation. RIG-I prevents PD-L1 destruction by SPOP ( 101 ).…”

Myeloid signature in the tumor immune microenvironment impacts the prognosis of urachal carcinoma

“…Foxp3, acting as a master switch for Treg, plays a crucial role in maintaining immune tolerance and suppressing autoimmunity, and is negatively correlated with colorectal cancer differentiation [20][21]. Furthermore, PDL1, known to reduce T-cell activation signals and facilitate immune evasion by cancer cells, emerges as a pivotal target for immunotherapy [22]. The outcomes revealed a signi cant increase in Foxp3, PDL1, CD8, GZMB, CD11b, MHC-I, and CD163 in the high-risk group, excluding CD68 (Fig.…”