RIG-I-Like Receptor LGP2 Is Required for Tumor Control by Radiotherapy

• Published in: Cancer research (Chicago, Ill.) Ill.), 2020-12, Vol.80 (24), p.5633-5641
• Main Authors: Zheng, Wenxin, Ranoa, Diana Rose E, Huang, Xiaona, Hou, Yuzhu, Yang, Kaiting, Poli, Elizabeth C, Beckett, Michael A, Fu, Yang-Xin, Weichselbaum, Ralph R
• Format: Article
• Language: English
• Subjects: Animals; CD8-Positive T-Lymphocytes; Cell Line, Tumor; DEAD Box Protein 58 - genetics; DEAD Box Protein 58 - metabolism; Dendritic Cells - pathology; Dendritic Cells - radiation effects; Female; Gene Expression Regulation, Neoplastic; Humans; Interferon-gamma - metabolism; Interferon-Induced Helicase, IFIH1 - genetics; Interferon-Induced Helicase, IFIH1 - metabolism; Mice, Inbred C57BL; Mice, Transgenic; Poly I-C - pharmacology; Radiation, Ionizing; Receptors, Immunologic - genetics; Receptors, Immunologic - metabolism; RNA Helicases - genetics; RNA Helicases - metabolism; Triple Negative Breast Neoplasms - drug therapy; Triple Negative Breast Neoplasms - genetics; Triple Negative Breast Neoplasms - mortality; Triple Negative Breast Neoplasms - radiotherapy
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-20-2324

Dendritic cells (DC) play an essential role in innate immunity and radiation-elicited immune responses. LGP2 is a RIG-I-like receptor involved in cytoplasmic RNA recognition and antiviral responses. Although LGP2 has also been linked to cell survival of both tumor cells and T cells, the role of LGP2 in mediating DC function and antitumor immunity elicited by radiotherapy remains unclear. Here, we report that tumor DCs are linked to the clinical outcome of patients with breast cancer who received radiotherapy, and the presence of DC correlates with gene expression of LGP2 in the tumor microenvironment. In preclinical models, host LGP2 was essential for optimal antitumor control by ionizing radiation (IR). The absence of LGP2 in DC dampened type I IFN production and the priming capacity of DC. In the absence of LGP2, MDA5-mediated activation of type I IFN signaling was abrogated. The MDA5/LGP2 agonist high molecular weight poly I:C improved the antitumor effect of IR. This study reveals a previously undefined role of LGP2 in host immunity and provides a new strategy to improve the efficacy of radiotherapy. SIGNIFICANCE: These findings reveal an essential role of LGP2 in promoting antitumor immunity after radiotherapy and provide a new strategy to enhance radiotherapy.