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 1

Low HLA-I APM expression correlates with nonresponsiveness to anti–CTLA-4 therapy and poor clinical outcome.

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Low HLA-I APM expression correlates with nonresponsiveness to anti–CTLA-...
(A) Schematic representation of HLA-I APM components. (B) Overall survival (OS) in the TCGA SKCM cohort (n = 462) stratified by high and low HLA-I APM (HLA-A, HLA-B, HLA-C, B2M, LMP2, LMP7, TAP1, TAP2, TAPBP) expression relative to the median, log-rank test. (C and D) Clinical relevance of altered HLA-I APM expression in an anti–CTLA-4–treated (αCTLA-4–treated) patient cohort (30). (C) Volcano plot showing overall upregulation of HLA-I APM genes in clinical responders (n = 14) versus nonresponders (n = 23) in the αCTLA-4–treated cohort. The x axis is the negative log10 value of the Mann-Whitney U P value; the y axis is the difference in mean rank between response groups. Red vertical dashed line, unadjusted P value of 0.05. (D) Kaplan-Meier survival curves of OS and PFS of high (n = 21) and low (n = 21) HLA-I APM expression groups, log-rank test. High and low expression groups were classified relative to the median HLA-I APM expression level in the entire cohort. (E) Clinical history of melanoma patient UKE-Mel-105 (ICB nonresponder). Horizontal line, time axis; above: diagnosis, therapeutic regimens, death; below: metastases development; arrows indicate cell lines established from metastases UKE-Mel-105b and UKE-Mel-105c. (F and G) Melanoma cells were transfected with 3pRNA, control (ctrl) RNA, or treated with IFNα-2a (IFNα) and subjected to further analysis following an incubation of 20 to 24 hours. HLA-I surface expression was measured by flow cytometry. (F) Representative histograms for UKE-Mel-105b and UKE-Mel-105c cells from 3 independent experiments. (G) HLA-I expression on Colo857 and Ma-Mel-54a melanoma cells. Relative MFI given as mean plus SEM, 2 independent experiments.