Tumor cell-intrinsic RIG-I in murine melanoma promotes checkpoint inhibitor-mediated anticancer immunity

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.