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 6

IFN-I–independent chemokine release and CD8+ T cell recruitment in response to RIG-I signaling.

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IFN-I–independent chemokine release and CD8+ T cell recruitment in respo...
(A–C) Ma-Mel-61g cells were transfected with 3pRNA or control (ctrl) RNA and subjected to further analyses following an incubation of 20 to 24 hours. (A) Ma-Mel-61g cells were transfected with RIG-I siRNA (siRIG-I) or control siRNA (siCtrl) 24 hours before 3pRNA or ctrl RNA transfection and subsequently analyzed for protein expression by immunoblot. GAPDH, loading control. Representative data from 3 independent experiments. (B) Chemokine mRNA expression determined by qPCR. Relative expression given as mean plus SEM from 2 independent experiments. (C) Cell culture supernatants were analyzed for CCL5 and CXCL10 content by ELISA. Chemokine levels given as mean plus SEM from 3 independent experiments. Significantly different experimental groups: *P < 0.05, **P < 0.01 by 2-tailed paired t test. (D) Schematic representation of the chicken CAM model. Ma-Mel-86c cells transplanted onto 2 distant sites of each CAM, autologous tumor–reactive CD8+ T cells injected into accessible vein. (E) Human Ma-Mel-86c tumors grown on chicken CAM were analyzed by immunohistochemistry. The 2 tumors on each CAM were treated with either 3pRNA (n = 4) or ctrl RNA (n = 4) on 2 consecutive days. At 24 hours after RNA application, autologous T cells were injected into the blood vessels of the embryo. Tumors were harvested 20 hours after T cell injection. Representative CD8 and HLA-I heavy chain staining shown for each group; original magnifications: ×10 (top), ×40 (bottom).