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

• Published in: The Journal of clinical investigation 2020-08, Vol.130 (8), p.4266-4281
• Main Authors: Such, Lina, Zhao, Fang, Liu, Derek, Thier, Beatrice, Le-Trilling, Vu Thuy Khanh, 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, Hartmann, Gunther, Becker, Jürgen C, Horn, Susanne, Ferrone, Soldano, Liu, David, Van Allen, Eliezer M, Schadendorf, Dirk, Griewank, Klaus, Trilling, Mirko, Paschen, Annette
• Format: Article
• Language: English
• Subjects: Animals; Antigens; Biological response modifiers; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - pathology; Cell Line, Tumor; DEAD Box Protein 58 - genetics; DEAD Box Protein 58 - immunology; Development and progression; Gene Silencing; Humans; Immunity, Cellular; Immunotherapy; Interferon; Medical research; Melanoma; Melanoma, Experimental - genetics; Melanoma, Experimental - immunology; Melanoma, Experimental - pathology; Melanoma, Experimental - therapy; Mice; Mice, Inbred NOD; Mice, SCID; Neoplasm Proteins - genetics; Neoplasm Proteins - immunology; Receptors, Immunologic; RNA; T cells; Xenograft Model Antitumor Assays
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI131572

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.