Immune Cell-Poor Melanomas Benefit from PD-1 Blockade after Targeted Type I IFN Activation

Tobias Bald, Jennifer Landsberg, Dorys Lopez-Ramos, Marcel Renn, Nicole Glodde, Philipp Jansen, Evelyn Gaffal, Julia Steitz, Rene Tolba, Ulrich Kalinke, Andreas Limmer, Göran B Jönsson, Michael Hoelzel, Thomas Tueting

Research output: Contribution to journalArticlepeer-review

Abstract

Infiltration of human melanomas with cytotoxic immune cells correlates with spontaneous type I IFN activation and a favorable prognosis. Therapeutic blockade of immune-inhibitory receptors in patients with preexisting lymphocytic infiltrates prolongs survival, but new complementary strategies are needed to activate cellular antitumor immunity in immune cell-poor melanomas. Here, we show that primary melanomas in Hgf-Cdk4(R24C) mice, which imitate human immune cell-poor melanomas with a poor outcome, escape IFN-induced immune surveillance and editing. Peritumoral injections of immunostimulatory RNA initiated a cytotoxic inflammatory response in the tumor microenvironment and significantly impaired tumor growth. This critically required the coordinated induction of type I IFN responses by dendritic, myeloid, natural killer, and T cells. Importantly, antibody-mediated blockade of the IFN-induced immune-inhibitory interaction between PD-L1 and PD-1 receptors further prolonged the survival. These results highlight important interconnections between type I IFNs and immune-inhibitory receptors in melanoma pathogenesis, which serve as targets for combination immunotherapies. SIGNIFICANCE: Using a genetically engineered mouse melanoma model, we demonstrate that targeted activation of the type I IFN system with immunostimulatory RNA in combination with blockade of immune-inhibitory receptors is a rational strategy to expose immune cell-poor tumors to cellular immune surveillance. (C) 2014 AACR.
Original languageEnglish
Pages (from-to)674-687
JournalCancer Discovery
Volume4
Issue number6
DOIs
Publication statusPublished - 2014

Subject classification (UKÄ)

  • Cancer and Oncology
  • Dermatology and Venereal Diseases

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