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

Abstract

Infi ltration 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 infi ltrates 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 infl ammatory response in the tumor microenvironment and signifi cantly impaired tumor growth. This critically required the coordinated induction of type I IFN responses by dendritic, myeloid, natural killer, and T cells. Importantly, antibodymediated 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. Cancer Discov; 4(6);

Dinaciclib induces immunogenic cell death and enhances anti-PD1–mediated tumor suppression

“…ICD-inducing agents, including anthracyclines, radiation therapy, and oncolytic viruses, have been shown to upregulate type I IFN response genes within the tumor cell (30,50,(60)(61)(62)(63)(64). Induction of the type I IFN response can be protective in preclinical tumor models, and combination treatment with anti-PD1 has been shown to significantly prolong survival over monotherapy (65,53). Recently, induction of a type I IFN response via radiation therapy was shown to overcome tumor resistance to anti-PD1 (64).…”

PD-1hi Identifies a Novel Regulatory B-cell Population in Human Hepatoma That Promotes Disease Progression

“…In contrast, PD-1 is upregulated on T cells, which leads to exhaustion of these cells in most solid tumors ( 4,5 ). Blocking the interaction between PD-1 and PD-L1 can restore T-cell function and result in tumor regression in both humans and mice (6)(7)(8)(9). Nevertheless, it should be emphasized that, in addition to being expressed on exhausted T cells, PD-1 can be rapidly upregulated on B cells, natural killer T cells, monocytes, and dendritic cells in infl amed tissues (10)(11)(12)(13), suggesting that PD-1-associated cancer therapy targets not only T cells but also the whole immune system.…”

Role of poly(ε-caprolactone) lipid-core nanocapsules on melanoma–neutrophil crosstalk

“…18,21 Recently, the role of pro-tumoral neutrophils on melanoma development and metastasis has been shown. 19,[22][23][24][25][26] The presence of neutrophils in the melanoma microenvironment is related to induction of angiogenesis, angiotropism and metastasis risk, showing that neutrophil secretion or its interaction with melanoma cells modifies the phenotype of melanoma cells. 26 Moreover, neutrophilia observed in metastatic melanoma 27 contributes to restrict tumor cells in the lung microcirculation, facilitating the melanoma transendothelial migration into tissue.…”

“…42 Blood neutrophilia and massive accumulation of neutrophils in melanoma tissue favor the development of the tumor, angiogenesis and melanoma dissemination. 19,[22][23][24][25][26] Therefore, a crosstalk between melanoma cells and neutrophils may be pivotal to tumor progression. [7][8][9][10][11][12] Herein, we showed that pre-incubation of melanoma cells with the nanocapsules affects the crosstalk between neutrophils/melanoma, as we observed by higher percentage of death in LNC-or AcE-LNC-pretreated melanoma cells co-incubated with neutrophils.…”