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.

• Authors: Simon Heidegger, Alexander Wintges, Florian Stritzke, Sarah Bek, Katja Steiger, Paul-Albert Koenig, Sascha Göttert, Thomas Engleitner, Rupert Öllinger, Tatiana Nedelko, Julius C Fischer, Vladimir Makarov, Christof Winter, Roland Rad, Marcel R M van den Brink, Jürgen Ruland, Florian Bassermann, Timothy A Chan, Tobias Haas, Hendrik Poeck
• Journal: Science immunology (Sci Immunol) Vol. 4 Issue 39 (09 13 2019) ISSN: 2470-9468 [Electronic] United States
• PMID: 31519811 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Chemical References

• Ddx58 protein, mouse
• DEAD Box Protein 58

Topics

• Animals
• Cell Line, Tumor
• Cohort Studies
• DEAD Box Protein 58 (genetics, immunology)
• Disease Models, Animal
• Humans
• Immunotherapy
• Melanoma (immunology, pathology, therapy)
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, Knockout
• Tumor Microenvironment