Inhibition of NK Reactivity Against Solid Tumors by Platelet-Derived RANKL.

Kim Clar,Clemens Hinterleitner,Stefanie Maurer,Pascal Schneider,Helmut Salih

doi:10.3390/cancers11030277

Kim Clar, Clemens Hinterleitner + Show 3 more

Open Access

https://doi.org/10.3390/cancers11030277

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Abstract

NK cells play an important role in tumor immunosurveillance. Their reactivity is governed by various activating and inhibitory surface receptors, which include several members of the TNF/TNF receptor family. For more than 50 years, it has been recognized that tumor immunosurveillance and in particular NK cell antitumor reactivity is largely influenced by platelets, but the underlying mechanisms remain to be fully elucidated. Here we report that upon activation, which reportedly occurs following interaction with cancer cells, platelets upregulate the TNF family member RANKL. Comparative analysis of the expression of RANK among different NK cell subsets and RANKL on platelets in cancer patients and healthy volunteers revealed a distinct malignant phenotype, and platelet-derived RANKL was found to inhibit the activity of normal NK cells against cancer cells. Notably, NK cell antitumor reactivity could be partially restored by application of denosumab, a RANKL-neutralizing antibody approved for treatment of benign and malignant osteolysis. Together, our data not only unravel a novel mechanism of tumor immune evasion mediated by platelets, but they also provide a functional explanation for the clinical observation that denosumab, beyond protecting from bone loss, may prolong disease-free survival in patients with solid tumors.

Highlights

The key role of platelets in tumor progression and metastasis has been recognized for more than 50 years [1]
We provided first evidence for the involvement of members of the TNF family in platelet-mediated evasion of tumor cells from natural killer (NK) cell reactivity: we showed that platelets transfer glucocorticoid-induced TNF receptor (TNFR)-related ligand (GITRL) to tumor cells, which results in diminished antitumor immunity due to triggering the GITR receptor that is expressed on and inhibits reactivity of NK cells [16]
No profound differences were observed between patients and healthy donors (HD), even if biometrical analysis revealed a small statistically significant difference for HVEM in T cells of CC and OX40 in T cells of breast cancer (BC) patients compared to HD (BC, p = 0.0125, ordinary one-way ANOVA with subsequent Dunnett’s multiple comparisons test; CC, p = 0.0206, Kruskal-Wallis test with subsequent Dunnett’s multiple comparisons test)

Summary

Introduction

The key role of platelets in tumor progression and metastasis has been recognized for more than 50 years [1]. Platelets interact with blood-borne tumor cells forming platelet-tumor cell aggregates, which enhance metastasis via multiple mechanisms. Beyond releasing growth factors/chemokines, facilitating endothelial adhesion and inducing epithelial-to-mesenchymal transition of tumor cells, platelets contribute to immune evasion, another hallmark of cancer [2,3,4]. Nieswandt and colleagues observed an inhibition of metastasis formation in thrombopenic mice, while additional depletion of natural killer (NK) cells reverted this effect, suggesting that platelets guard tumor cells against elimination by NK cells [5]. NK cell effector function, which is regulated by integration of multiple inhibitory and activating signals mediated by various immunoregulatory molecules, plays a key role in controlling metastatic dissemination [6,7]. We contributed to a better understanding of the mechanisms by which

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