TY - JOUR AU - Such, Lina AU - Zhao, Fang AU - Liu, Derek AU - Thier, Beatrice AU - Le-Trilling, Vu Thuy Khanh AU - Sucker, Antje AU - Coch, Christoph AU - Pieper, Natalia AU - Howe, Sebastian AU - Bhat, Hilal AU - Kalkavan, Halime AU - Ritter, Cathrin AU - Brinkhaus, Robin AU - Ugurel, Selma AU - Köster, Johannes AU - Seifert, Ulrike AU - Dittmer, Ulf AU - Schuler, Martin AU - Lang, Karl S. AU - Kufer, Thomas A. AU - Hartmann, Gunther AU - Becker, Jürgen C. AU - Horn, Susanne AU - Ferrone, Soldano AU - Liu, David AU - Van Allen, Eliezer M. AU - Schadendorf, Dirk AU - Griewank, Klaus AU - Trilling, Mirko AU - Paschen, Annette T1 - Targeting the innate immunoreceptor RIG-I overcomes melanoma-intrinsic resistance to T cell immunotherapy PY - 2020/08/03/ AB - 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. JF - The Journal of Clinical Investigation JA - J Clin Invest SN - 0021-9738 DO - 10.1172/JCI131572 VL - 130 IS - 8 UR - https://doi.org/10.1172/JCI131572 SP - 4266 EP - 4281 PB - The American Society for Clinical Investigation ER -