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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.
Subject of Study
Subject(s)
OncoTree Cancer Type(s)
Melanoma
Access via ENA

36 Murine tumor RNA-sequence datasets
Accession #: PRJEB32241

Access Restrictions
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
Nextseq 500 System
Dataset Format(s)
FASTQ, SRA, TAR, gzip
Dataset Size
5Gb (FASTQ)
Data Catalog Record Updated
2021-10-26