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

Bald, Tobias; Landsberg, Jennifer; Lopez-Ramos, Dorys; Renn, Marcel; Glodde, Nicole; Jansen, Philipp; Gaffal, Evelyn; Steitz, Julia; Tolba, Rene and Kalinke, Ulrich, et al. (2014) In Cancer Discovery 4(6). p.674-687
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... (More)
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. (Less)
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Cancer Discovery
volume
4
issue
6
pages
674 - 687
publisher
American Association for Cancer Research
external identifiers
  • wos:000337185500024
  • scopus:84904055758
ISSN
2159-8274
DOI
10.1158/2159-8290.CD-13-0458
language
English
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yes
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9b407659-e8e8-4910-84f1-a0d23f6cfc10 (old id 4549142)
date added to LUP
2014-08-01 07:38:02
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2017-10-29 03:14:03
@article{9b407659-e8e8-4910-84f1-a0d23f6cfc10,
  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.},
  author       = {Bald, Tobias and Landsberg, Jennifer and Lopez-Ramos, Dorys and Renn, Marcel and Glodde, Nicole and Jansen, Philipp and Gaffal, Evelyn and Steitz, Julia and Tolba, Rene and Kalinke, Ulrich and Limmer, Andreas and Jönsson, Göran B and Hoelzel, Michael and Tueting, Thomas},
  issn         = {2159-8274},
  language     = {eng},
  number       = {6},
  pages        = {674--687},
  publisher    = {American Association for Cancer Research},
  series       = {Cancer Discovery},
  title        = {Immune Cell-Poor Melanomas Benefit from PD-1 Blockade after Targeted Type I IFN Activation},
  url          = {http://dx.doi.org/10.1158/2159-8290.CD-13-0458},
  volume       = {4},
  year         = {2014},
}