Targeting the innate immunoreceptor RIG-I overcomes melanoma-intrinsic resistance to T cell immunotherapy
Lina Such, … , Mirko Trilling, Annette Paschen
Lina Such, … , Mirko Trilling, Annette Paschen
Published May 19, 2020
Citation Information: J Clin Invest. 2020;130(8):4266-4281. https://doi.org/10.1172/JCI131572.
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Research Article Immunology Oncology

Targeting the innate immunoreceptor RIG-I overcomes melanoma-intrinsic resistance to T cell immunotherapy

Abstract

Understanding tumor resistance to T cell immunotherapies is critical to improve patient outcomes. Our study revealed a role for transcriptional suppression of the tumor-intrinsic HLA class I (HLA-I) antigen processing and presentation machinery (APM) in therapy resistance. Low HLA-I APM mRNA levels in melanoma metastases before immune checkpoint blockade (ICB) correlated with nonresponsiveness to therapy and poor clinical outcome. Patient-derived melanoma cells with silenced HLA-I APM escaped recognition by autologous CD8+ T cells. However, targeted activation of the innate immunoreceptor RIG-I initiated de novo HLA-I APM transcription, thereby overcoming T cell resistance. Antigen presentation was restored in interferon-sensitive (IFN-sensitive) but also immunoedited IFN-resistant melanoma models through RIG-I–dependent stimulation of an IFN-independent salvage pathway involving IRF1 and IRF3. Likewise, enhanced HLA-I APM expression was detected in RIG-Ihi (DDX58hi) melanoma biopsies, correlating with improved patient survival. Induction of HLA-I APM by RIG-I synergized with antibodies blocking PD-1 and TIGIT inhibitory checkpoints in boosting the antitumor T cell activity of ICB nonresponders. Overall, the herein-identified IFN-independent effect of RIG-I on tumor antigen presentation and T cell recognition proposes innate immunoreceptor targeting as a strategy to overcome intrinsic T cell resistance of IFN-sensitive and IFN-resistant melanomas and improve clinical outcomes in immunotherapy.

Authors

Lina Such, Fang Zhao, Derek Liu, Beatrice Thier, Vu Thuy Khanh Le-Trilling, Antje Sucker, Christoph Coch, Natalia Pieper, Sebastian Howe, Hilal Bhat, Halime Kalkavan, Cathrin Ritter, Robin Brinkhaus, Selma Ugurel, Johannes Köster, Ulrike Seifert, Ulf Dittmer, Martin Schuler, Karl S. Lang, Thomas A. Kufer, Gunther Hartmann, Jürgen C. Becker, Susanne Horn, Soldano Ferrone, David Liu, Eliezer M. Van Allen, Dirk Schadendorf, Klaus Griewank, Mirko Trilling, Annette Paschen

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Figure 4

IRF1 and IRF3 mediate IFN-independent HLA-I APM upregulation upon RIG-I activation.

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IRF1 and IRF3 mediate IFN-independent HLA-I APM upregulation upon RIG-I ...
(A–D) Melanoma cells Ma-Mel-86c and fibrosarcoma cells U3A (STAT1–/–) and U5A (IFNAR2c–/–) were transfected with 3pRNA (+) or control RNA (–) and subjected to further analysis following an incubation of 20 to 24 hours. (A and B) Representative (p)STAT1 (A), IRF1 (A), (p)IRF3 (B), and NLRC5 (A) immunoblots from 3 independent experiments. GAPDH, loading control. (C and D) Ma-Mel-86c and U3A cells were transfected with siRNA targeting IRF3 (siIRF3) (C), IRF1 (siIRF1) (C), NLRC5 (siNLRC5) (D), or control siRNA (siCtrl) (C and D) 24 hours before 3pRNA (+) or control RNA (–) transfection. Protein expression was analyzed by immunoblot. GAPDH, loading control. Representative data from 3 independent experiments.