Tumor cell-intrinsic RIG-I in murine melanoma promotes checkpoint inhibitor-mediated anticancer immunity
UID: 10376
Publisher(s): Klinik und Poliklinik für Innere Medizin II, Klinikum rechts der Isar Technische Universität München- Description
- Durable clinical responses to immune checkpoint inhibitors (ICB) remain limited to a minority of patients, and the molecular pathways that modulate ICB efficacy remain incompletely defined. Here we demonstrate that immunotherapy with anti-CTLA-4 and its combination with anti-PD-1 rely on melanoma cell-intrinsic activation of the cytosolic RNA receptor RIG-I. Mechanistically, tumor cell-intrinsic RIG-I signaling induced caspase-3-mediated tumor cell death, cross-presentation of tumor-associated antigen by CD103+ dendritic cells, subsequent expansion of tumor antigen-specific CD8+ T cells, and their accumulation within the tumor tissue. Consistently, therapeutic targeting of RIG-I with 5’-phosphorylated-RNA in both tumor and non-malignant host cells potently augmented the efficacy of CTLA-4 checkpoint blockade in several preclinical cancer models. In humans, transcriptome analysis of primary melanoma samples revealed a strong association between high expression of DDX58 (the gene encoding RIG-I), T cell receptor and antigen presentation pathway activity and prolonged overall survival. Moreover, in melanoma patients treated with anti-CTLA-4 checkpoint blockade, high RIG-I transcriptional activity significantly associated with durable clinical responses. Our data thus identify activation of RIG-I signaling in tumors and their microenvironment as a crucial component for checkpoint inhibitor-mediated immunotherapy of cancer.
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Access via ENA
36 Murine tumor RNA-sequence datasets
Accession #: PRJEB32241 - Access Restrictions
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Free to All
- Access Instructions
- Data is publicly available via the European Nucleotide Archive for download in FASTQ tar files or SRA (Sequence Read Archive) files
- Associated Publications
- Data Type
- Equipment Used
- Dataset Format(s)
- FASTQ, SRA, TAR, gzip
- Dataset Size
- 5Gb (FASTQ)
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