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- Title
Targeting the innate immunoreceptor RIG-I overcomes melanoma-intrinsic resistance to T cell immunotherapy.
- Authors
Such, Lina; Zhao, Fang; Liu, Derek; Thier, Beatrice; Khanh Le-Trilling, Vu Thuy; Sucker, Antje; Coch, Christoph; Pieper, Natalia; Howe, Sebastian; Bhat, Hilal; Kalkavan, Halime; Ritter, Cathrin; Brinkhaus, Robin; Ugurel, Selma; Köster, Johannes; Seifert, Ulrike; Dittmer, Ulf; Schuler, Martin; Lang, Karl S.; Kufer, Thomas A.
- 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.
- Subjects
T cells; CELLULAR recognition; TUMOR antigens; ANTIGEN presentation; ANTIGEN processing; MELANOMA treatment; PROTEINS; RESEARCH; MELANOMA; ANIMAL experimentation; RESEARCH methodology; EVALUATION research; MEDICAL cooperation; COMPARATIVE studies; GENES; RESEARCH funding; CELLULAR immunity; CELL lines; IMMUNOTHERAPY; MICE
- Publication
Journal of Clinical Investigation, 2020, Vol 130, Issue 8, p4266
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI131572