RIG-I immunotherapy overcomes radioresistance in p53-positive malignant melanoma

Abstract

Radiotherapy induces DNA damage, resulting in cell-cycle arrest and activation of cell-intrinsic death pathways. However, radioresistance of some tumor entities such as malignant melanoma limits its clinical application. The innate immune sensing receptor RIG-I is ubiquitously expressed and upon activation triggers an immunogenic form of cell death in a variety of tumor cell types including melanoma. To date, the potential of RIG-I ligands to overcome radioresistance of tumor cells has not been investigated. Here, we demonstrate that RIG-I activation enhanced the extent and immunogenicity of irradiation-induced tumor cell death in human and murine melanoma cells in vitro and improved survival in the murine B16-melanoma model in vivo. Transcriptome analysis pointed to a central role for p53 which was confirmed using p53–/– B16 cells. In vivo, the additional effect of RIG-I in combination with irradiation on tumor growth was absent in mice carrying p53–/– B16 tumors, while the antitumoral response to RIG-I stimulation alone was maintained. Our results identify p53 as a pivotal checkpoint which is triggered by RIG-I resulting in enhanced irradiation-induced tumor cell death. Thus, the combined administration of RIG-I ligands and radiotherapy is a promising approach to treat radioresistant tumors with a functional p53 pathway, such as melanoma.

Enhancing Immunogenicity in Metastatic Melanoma: Adjuvant Therapies to Promote the Anti-Tumor Immune Response

“…ICD can also be induced via innate immune system pathways. For example, retinoic acid-inducible gene I (RIG-I) is a cytosolic RNA sensor that, when stimulated, can induce ICD via the interferon-dependent apoptosis of melanoma cells [ 79 , 80 , 81 ]. RIG-I agonists, such as M8, can be used to activate the RIG-I pathway, subsequently activating the innate immune system by increasing DC expression of the co-stimulatory factors CD80 and CD86, and further enhancing DCs’ ability to process antigens and cross-present to CD8+ T-cells [ 79 , 80 , 81 ].…”

Stimuli‐responsive nanodelivery systems for amplifying immunogenic cell death in cancer immunotherapy

“…The innate immune sensing receptor retinoic acid‐inducible gene 1 (RIG‐I) presents ubiquitous expression, and its activation provokes ICD in various cancer types 77 . RNA agonists of RIG‐I pathway represent an opportunity for clinically relevant cancer immunotherapy 78 .…”

“…The innate immune sensing receptor retinoic acid-inducible gene 1 (RIG-I) presents ubiquitous expression, and its activation provokes ICD in various cancer types. 77 RNA agonists of RIG-I pathway represent an opportunity for clinically relevant cancer immunotherapy. 78 The effects are impeded by drug delivery barriers, comprising nuclease degradation, unfavorable intracellular uptake as well as limited access to the RIG-I-localized cytosol.…”

The RIG-I agonist M8 triggers cell death and natural killer cell activation in human papillomavirus-associated cancer and potentiates cisplatin cytotoxicity

“…In particular, the activation of RIG-I signaling in cancer cells by specific agonists, such as 5’ppp-RNAs, triggered cancer cell death programs in either a type I IFN-dependent or -independent manner. Lastly, RIG-I signaling in cancer cells mediated the activation of several innate immunity cells, including dendritic cells (DCs), natural killer (NK) cells, and CD8 + T cells, thereby promoting cancer cell death [ 6 – 10 ].…”

“…Against this backdrop, PRR stimulation appears to be among the most promising therapeutic targets [ 6 – 10 ]. This is particularly true for HPV-infected cells where deregulated expression of the viral oncoproteins E6 and E7 leads to impaired innate immunity, thus allowing the virus to complete its life cycle and persist in the host cell, all the while boosting cell proliferation and promoting cancer development.…”