Innate RIG-I signaling restores antigen presentation in tumors and overcomes T cell resistance
Authors:Beatrice Thier1,2 and Annette Paschen1,2
1 Department of Dermatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
2 German Cancer Consortium (DKTK), University Hospital Essen, Essen, Germany.
Keywords:
tumor, HLA class I, T cell resistance, RIG-I, interferon, immune checkpoint blockade.
Corresponding Author(s):
Conflict of interest statement:
A. Paschen received research grant support and provision of reagents from BMS. The company had no input into the conception, conduct or reporting of the submitted work.
Please cite this article as:
Beatrice Thier and Annette Paschen (2021). Innate RIG-I signaling restores antigen presentation in tumors and overcomes T cell resistance. Cell Stress 5(2): 26-28. doi: 10.15698/cst2021.02.242
© 2021 Thier and Paschen. This is an open-access article released under the terms of the Creative Commons Attribution (CC BY) license, which allows the unrestricted use, distribution, and reproduc-tion in any medium, provided the original author and source are acknowledged.
Abstract:
In recent years, therapy with immune modulating antibodies, termed immune checkpoint blockade (ICB), has revolutionized the treatment of advanced metastatic melanoma, yielding long-lasting clinical responses in a subgroup of patients. But despite this remarkable progress, resistance to therapy represents a major clinical challenge. ICB efficacy is critically dependent on cytotoxic CD8+ T cells targeting tumor cells in an HLA class I (HLA-I) antigen-dependent manner. Transcriptional suppression of the HLA-I antigen processing and presentation machinery (HLA-I APM) in melanoma cells leads to HLA-I-low/-negative tumor cell phenotypes escaping CD8+ T cell recognition and contributing to ICB resistance. In general, HLA-I-low/-negative tumor cells can be re-sensitized to T cells by interferons (IFN), augmenting HLA-I APM expression. However, this mechanism fails when melanoma cells acquire resistance to IFN, which recently turned out as a key resistance mechanism in ICB, besides HLA-I APM suppression. Seeking for a strategy to overcome these barriers, we identified a novel mechanism that restores HLA-I antigen presentation in tumor cells independent of IFN (Such et al. (2020) J Clin Invest, doi: 10.1172/JCI131572). We demonstrated that tumor cell-intrinsic activation of the cytosolic innate immunoreceptor RIG-I by its synthetic ligand 3pRNA overcomes transcriptional HLA-I APM suppression in patient-derived IFN-resistant melanoma cells. De novo HLA-I APM expression is IRF1/IRF3-dependent and re-sensitizes melanoma cells to autologous cytotoxic CD8+ T cells. Notably, synthetic RIG-I ligands and ICB synergize in T cell activation, suggesting combinational therapy could be an efficient strategy to improve patient outcomes in melanoma.