Article Text

Download PDFPDF

L5 RIG-I activation enhances melanoma immunogenicity and improves anti-tumor T cell responses in combination with anti-PD-1 immune checkpoint blocking antibodies
  1. B Thier1,2,
  2. L Such1,2,
  3. M Schwamborn1,2,
  4. A Sucker1,2,
  5. C Coch3,
  6. D Schadendorf1,2,
  7. K Griewank1,2,
  8. M Trilling4,
  9. F Zhao1,2 and
  10. A Paschen1,2
  1. 1Dermatology, University Hospital Essen, Essen, Germany
  2. 2German Cancer Consortium (DKTK), Partner Site Essen/Düsseldorf, Essen, Germany
  3. 3Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Bonn, Germany
  4. 4Institute of Virology, University Hospital Essen, Essen, Germany


Background Clinical efficacy of immune checkpoint blocking (ICB) therapy critically relies on the killing of melanoma cells by CD8+ T cells, becoming activated upon recognition of tumor antigens presented by HLA class I (HLA-I) surface molecules. Patient-derived melanoma cells can escape from cytotoxic T cell effector functions by loss of HLA-I surface expression due to the silencing of HLA-I antigen processing and presentation machinery (APM) genes.

Material and Methods Seeking for a strategy to restore HLA-I expression, we transfected melanoma cells obtained from distinct patient metastasis with synthetic short double stranded RNA (3pRNA), an activating ligand of the cytosolic innate pattern recognition receptor RIG-I. 3pRNA-transfected melanoma cells were analyzed for HLA-I surface expression by FACS analysis and gene expression of HLA-I APM components by qPCR. In vivo 3pRNA-transfected tumors were analyzed for HLA-I expression by immunohistochemistry staining. Furthermore, T cell activation after coincubation with 3pRNA-transfected melanoma cells was determined by IFNγ-ELISpot assay. The effect of combined 3pRNA and blocking anti-PD-1 antibody treatment on T cell activation was measured by intracellular cytokine staining and FACS analysis.

Results Activation of RIG-I by 3pRNA increased the expression of HLA-I APM components and strongly enhanced recognition of melanoma cells by autologous CD8+ T cells. Based on these findings, we asked whether the combination of 3pRNA and blocking anti-PD-1 antibodies could improve anti-melanoma T cell responses in an anti-PD-1 non-responder patient model. Indeed, T cell activation by 3pRNA-transfected melanoma cells was significantly increased in the presence of anti-PD-1 antibodies. In line with the enhancement of anti-tumor T cell responses, we found an association of elevated RIG-I mRNA levels with prolonged patient survival in TCGA melanoma samples.

Conclusions In summary, this study demonstrates a beneficial effect of RIG-I activation on antigen presentation and T cell recognition of melanoma cells. Improved T cell responses by combined 3pRNA and anti-PD-1 treatment suggests that combinational therapy could be a strategy to overcome T cell resistance in melanoma.

Disclosure Information B. Thier: None. L. Such: None. M. Schwamborn: None. A. Sucker: None. C. Coch: None. D. Schadendorf: None. K. Griewank: None. M. Trilling: None. F. Zhao: None. A. Paschen: None.

Statistics from

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.