Natural Killer Group 2D Ligand Depletion Reconstitutes Natural Killer Cell Immunosurveillance of Head and Neck Squamous Cell Carcinoma.

Sandra Weil,Eva Herrmann,Andreas Müller-Runte,Axel Lechner,Dirk Beutner,Alexander Steinle,Joachim Koch,Volker Huppert,Karen Lampe,Stefanie Memmer,Ralf Schubert,Alexander Quaas,Michael S Von Bergwelt-Baildon,Lutz Walter,Ariane Giannattasio,Tamara Becker,Ulrike Koehl

doi:10.3389/fimmu.2017.00387

Abstract

Head and neck squamous cell carcinoma (HNSCC) is a highly heterogeneous and aggressive tumor originating from the epithelial lining of the upper aero-digestive tract accounting for 300,000 annual deaths worldwide due to failure of current therapies. The natural killer group 2D (NKG2D) receptors on natural killer (NK) cells and several T cell subsets play an important role for immunosurveillance of HNSCC and are thus targeted by tumor immune evasion strategies in particular by shedding of various NKG2D ligands (NKG2DLs). Based on plasma and tumor samples of 44 HNSCC patients, we found that despite compositional heterogeneity the total plasma level of NKG2DLs correlates with NK cell inhibition and disease progression. Strikingly, based on tumor spheroids and primary tumors of HNSCC patients, we found that NK cells failed to infiltrate HNSCC tumors in the presence of high levels of NKG2DLs, demonstrating a novel mechanism of NKG2DL-dependent tumor immune escape. Therefore, the diagnostic acquisition of the plasma level of all NKG2DLs might be instrumental for prognosis and to decipher a patient cohort, which could benefit from restoration of NKG2D-dependent tumor immunosurveillance. Along these lines, we could show that removal of shed NKG2DLs (sNKG2DLs) from HNSCC patients’ plasma restored NK cell function in vitro and in individual patients following surgical removal of the primary tumor. In order to translate these findings into a therapeutic setting, we performed a proof-of-concept study to test the efficacy of adsorption apheresis of sNKG2DLs from plasma after infusion of human MICA in rhesus monkeys. Complete removal of MICA was achieved after three plasma volume exchanges. Therefore, we propose adsorption apheresis of sNKG2DLs as a future preconditioning strategy to improve the efficacy of autologous and adoptively transferred immune cells in cellular cancer immunotherapy.

Highlights

Head and neck squamous cell carcinoma (HNSCC) is a highly aggressive solid tumor originating from the epithelial lining of the upper aero-digestive tract and is characterized by phenotypic, etiological, biological, and clinical heterogeneity [1, 2]
natural killer group 2D (NKG2D)-dependent immune escape based on the release of shed NKG2D ligand (NKG2DL) (sNKG2DL) has been described in a variety of cancers [50, 51], but most studies mainly concentrated on sMICA and sMICB
In the present study, profiling of HNSCC plasma revealed that the cumulative level of the sNKG2DLs is patient specific, correlates with disease progression and tumor load, and is indicative for NKG2D-dependent tumor immune escape in HNSCC

Summary

Introduction

Head and neck squamous cell carcinoma (HNSCC) is a highly aggressive solid tumor originating from the epithelial lining of the upper aero-digestive tract and is characterized by phenotypic, etiological, biological, and clinical heterogeneity [1, 2]. NK cells mediate immunosurveillance of malignantly transformed cells [15, 16] Their cytotoxicity is regulated by a dynamic balance of agonistic and antagonistic signaling from activating and inhibitory receptors [16]. Among the major activating receptors is the natural killer group 2D (NKG2D) receptor [17,18,19], which is expressed on T cell subtypes and NKT cells [20]. Patients suffering from various cancers [27,28,29,30,31,32,33] demonstrated an inverse correlation of sMICA plasma levels and NKG2D-dependent NK cell cytotoxicity. The majority of studies so far investigated only individual sNKG2DLs

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Conclusion