Immune Cell–Poor Melanomas Benefit from PD-1 Blockade after Targeted Type I IFN Activation
- 1 June 2014
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Discovery
- Vol. 4 (6), 674-687
- https://doi.org/10.1158/2159-8290.cd-13-0458
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-Cdk4R24C 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.Keywords
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