Upregulation of RIG-I is Critical for Responsiveness to IFN-α Plus Anti-PD-1 in Colorectal Cancer.

BACKGROUNDS: Immunotherapy is a promising and effective approach that has achieved significant curative effects in colorectal cancer (CRC). Recently, retinoic acid-inducible gene I (RIG-I) has been shown to play a critical role in tumor immunity. However, the correlation between RIG-I and immunotherapy in CRC remains unclear. METHODS: RIG-I expression was measured in CRC and normal samples based on analysis of the public databases, a tissue microarray, and CRC cell lines. The correlation between RIG-I and immune microenvironment was explored using well-established biological algorithms and in vitro and in vivo experiments. RESULTS: We discovered that RIG-I expression was downregulated in CRC compared with normal samples. The bioinformatic algorithms indicated that high RIG-I-expressing samples showed a positive correlation with IFN-α response and enrichment of antitumor immune cells, especially CD8+ T cells. Furthermore, knockdown of RIG-I expression efficiently reduced the cell death, STAT1 phosphorylation, and CXCL10/11 expression induced by IFN-α in CRC cells. Finally, an in vivo study showed that the infiltration of CD3+ CD8+ T cells was significantly decreased in the RIG-I knockout group. An animal model further confirmed that the inhibition of tumor growth induced by IFN-α plus anti-PD-1 therapy was dependent on RIG-I expression. CONCLUSION: RIG-I is a promising biomarker for CRC immunotherapy, which provides a novel concept for combinatorial immunotherapy.