RIG-I activation is critical for responsiveness to checkpoint blockade

Abstract

Achieving durable clinical responses to immune checkpoint inhibitors remains a challenge. Here, we demonstrate that immunotherapy with anti–CTLA-4 and its combination with anti–PD-1 rely on tumor 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′– triphosphorylated RNA in both tumor and nonmalignant 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 patients with melanoma treated with anti–CTLA-4 checkpoint blockade, high DDX58 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.

RNA-seq Analysis of Wild-Type vs. FOXC2-Deficient Melanoma Cells Reveals a Role for the FOXC2 Transcription Factor in the Regulation of Multiple Oncogenic Pathways

“…FOXC2 expression was also associated with downregulation of various IFN-stimulated genes, including Oas1a, Oas1g, Isg15, Ifi27, Ifi35, Ifitm3, Ifit1, and Ifit3, among others. In keeping with our observation of FOXC2-associated downregulation of Ddx58 expression and the aforementioned link between FOXC2 expression and poor PFS of melanoma patients on ipilimumab, it is worth noting that Heidegger et al recently demonstrated the importance of tumor cell-intrinsic activation of RIG-I in the success of checkpoint blockade therapy (38). Interestingly, RIG-I deficiency in cancer cells was also recently linked to the induction of tolerogenic dendritic cells (39), a cell type that could impact the efficacy of several immune-based therapies and one that is of particular interest to our laboratory (40,41).…”

DUSP11-mediated control of 5′-triphosphate RNA regulates RIG-I sensitivity

“…Recent work established the validity of activating PRRs as a strategy to enhance a therapeutic immune response against tumors. Agonists of STING and RIG-I have shown promise in mouse models as standalone or adjuvants for enhancing immunotherapies (Elion et al 2018;Ramanjulu et al 2018;Heidegger et al 2019;Jiang et al 2019). Conversely, in some contexts, interferon signaling is beneficial to tumor growth (Khodarev et al 2012;Boelens et al 2014;Nabet et al 2017).…”

High RIG‐I expression in ovarian cancer associates with an immune‐escape signature and poor clinical outcome

“…However, given adequate stratification based on predictive biomarkers, checkpoint inhibition may still be a valuable option in OC, particularly as an adjuvant treatment after primary surgical cytoreduction. It remains to be seen whether RIG-I expression can refine such stratification and inform PD-L1 targeted therapy in a residual disease setting: while responsiveness to checkpoint inhibition depends at least in part on RIG-I activation, 57 RIG-I associated interferon expression may in turn counteract the efficacy of this immunotherapeutic modality. 58 In this regard, it is important to note that ISGs expressed by cancer and immune cells are differentially associated with responsiveness to checkpoint inhibition despite their expression being positively correlated (explainable by a threshold phenomenon).…”