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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

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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 8

Combination of 3pRNA and ICB improves TIL reactivity toward autologous melanoma cells.

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Combination of 3pRNA and ICB improves TIL reactivity toward autologous m...
(A) Clinical history of melanoma patient UKE-Mel-154. Horizontal line, time axis; above: diagnosis, therapeutic regimens, death; below: UKE-Mel-154c melanoma cell and CD8+ TILs obtained from lymph node (LN) metastasis. (B) HLA-I and ICAM-1 surface expression on 3pRNA- and ctrl RNA–transfected UKE-Mel-154c cells. Representative histograms from 3 independent experiments. (C) Volcano plot showing overall upregulation of HLA-I APM genes in clinical responders (n = 57) versus nonresponders (n = 62) in the αPD-1–treated cohort (39). 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 and E) Scatterplot of RIG-I (DDX58) pathway expression against HLA-I APM expression across all samples in the αPD-1 (n = 121) and αCTLA-4 (n = 42) cohort. (F and G) PD-L1 and CD155 surface expression on 3pRNA- or ctrl RNA–transfected UKE-Mel-154c cells. (F) Representative histograms, (G) relative MFI given as mean plus SEM from 3 independent experiments. (H) Representative PD-1 and TIGIT surface expression on TILs from 3 independent experiments. (I and J) Combination of targeted RIG-I activation and ICB enhances TIL reactivity toward autologous melanoma cells. (I) Concurrent treatment. TIL activation after 4-hour coincubation with 3pRNA- or ctrl RNA–treated UKE-Mel-154c cells in the presence of PD-1 or αTIGIT antibodies, by intracellular cytokines staining (ICS). (J) Sequential treatment. After 7-day preincubation with irradiated (irr.) UKE-Mel-154c cells in the absence or presence of αPD-1 or αTIGIT antibodies, TILs were harvested and activation was measured after 4-hour coincubation with 3pRNA- or ctrl RNA–treated UKE-Mel-154c cells. (I and J) Mean plus SEM fold change in frequency of IFN-γ+CD8+ T cells stimulated by ctrl RNA–transfected UKE-Mel-154c cells from 3 independent experiments. (G, I, and J) Significantly different experimental groups: *P < 0.05, **P < 0.01, ***P < 0.005 by 2-tailed paired t test.

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