RIG-I activation is critical for responsiveness to checkpoint blockade Journal Article
| Authors: | Heidegger, S.; Wintges, A.; Stritzke, F.; Bek, S.; Steiger, K.; Koenig, P. A.; Göttert, S.; Engleitner, T.; Öllinger, R.; Nedelko, T.; Fischer, J. C.; Makarov, V.; Winter, C.; Rad, R.; van den Brink, M. R. M.; Ruland, J.; Bassermann, F.; Chan, T. A.; Haas, T.; Poeck, H. |
| Article Title: | 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. Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. |
| Journal Title: | Science Immunology |
| Volume: | 4 |
| Issue: | 39 |
| ISSN: | 2470-9468 |
| Publisher: | Amer Assoc Advancement Science |
| Date Published: | 2019-09-13 |
| Start Page: | eaau8943 |
| Language: | English |
| DOI: | 10.1126/sciimmunol.aau8943 |
| PUBMED: | 31519811 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Source: Scopus |
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