RIG-I activation is critical for responsiveness to checkpoint blockade

Heidegger S, Wintges A, Stritzke F, Bek S, Steiger K, Koenig PA, Goettert S, Engleitner T, Oellinger R, Nedelko T, Fischer JC, Makarov V, Winter C, Rad R, Van Den Brink MRM, Ruland J, Bassermann F, Chan TA, Haas T, Poeck H (2019)

Publication Type: Journal article

Publication year: 2019

Journal

Science immunology American Association for the Advancement of Science

Book Volume: 4

Article Number: eaau8943

Journal Issue: 39

DOI: 10.1126/sciimmunol.aau8943

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.

Involved external institutions

Technische Universität München (TUM) DE Germany (DE) Deutsches Krebsforschungszentrum (DKFZ) DE Germany (DE) Memorial Sloan Kettering Cancer Center US United States (USA) (US)

How to cite

APA:

Heidegger, S., Wintges, A., Stritzke, F., Bek, S., Steiger, K., Koenig, P.-A.,... Poeck, H. (2019). RIG-I activation is critical for responsiveness to checkpoint blockade. Science immunology, 4(39). https://doi.org/10.1126/sciimmunol.aau8943

MLA:

Heidegger, Simon, et al. "RIG-I activation is critical for responsiveness to checkpoint blockade." Science immunology 4.39 (2019).

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