title: Increased sMICA and TGFβ1levels in HNSCC patients impair NKG2D-dependent functionality of activated NK cells.
abstract: Disseminated head-and-neck squamous cell carcinoma (HNSCC) escapes immune surveillance and thus frequently manifests as fatal disease. Here, we report on the distribution of distinct immune cell subpopulations, natural killer (NK) cell cytotoxicity and tumor immune escape mechanisms (TIEMs) in 55 HNSCC patients, either at initial diagnosis or present with tumor relapse. Compared to healthy controls, the regulatory NK cells and the ratio of pro/anti-inflammatory cytokines were decreased in HNSCC patients, while soluble major histocompatibility complex Class I chain-related peptide A (sMICA) and transforming growth factor β1(TGFβ1) plasma levels were markedly elevated. Increased sMICA and TGFβ1concentrations correlated with tumor progression and staging characteristics in 7 follow-up HNSCC patients, with significantly elevated levels of both soluble factors from the time of initial diagnosis to that of relapse. Patient plasma containing elevated sMICA and TGFβ1markedly impaired NKG2D-dependent cytotoxicity against HNSCC cells upon incubation with patient-derived and IL-2 activated NK cellsvs.those derived from healthy donors. Decreased antitumor recognition was accompanied by reduced NKG2D expression on the NK cell surface and an enhanced caspase-3 activity.In-vitroblocking and neutralization experiments demonstrated a synergistic negative impact of sMICA and TGFβ1on NK cell functionality. Although we previously showed the feasibility and safety of transfer of allogeneic donor NK cells in a prior clinical study encompassing various leukemia and tumor patients, our present results suggest the need for caution regarding the sole use of adoptive NK cell transfer. The presence of soluble NKG2D ligands in the plasma of HNSCC patients and the decreased NK cell cytotoxicity due to several factors, especially TGFβ1, indicates timely depletion of these immunosuppressing molecules may promote NK cell-based immunotherapy.
authors.affiliation: Institute for Cellular therapeutics; IFB-Tx; Hannover Medical School ; Hannover, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Klöß
authors.affiliation: Department of Oral; Cranio-Maxillofacial and Facial Plastic Surgery; Klinikum Hanau GmbH ; Hanau, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Chambron
authors.affiliation: Institute for Cellular therapeutics; IFB-Tx; Hannover Medical School ; Hannover, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Gardlowski
authors.affiliation: Institute for Cellular therapeutics; IFB-Tx; Hannover Medical School ; Hannover, Germany.
authors.forename: Lubomir
authors.initials: L
authors.lastname: Arseniev
authors.affiliation: Georg-Speyer-Haus; Institute for Tumor Biology and Experimental Therapy ; Frankfurt, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Koch
authors.affiliation: Institute for Cellular therapeutics; IFB-Tx; Hannover Medical School ; Hannover, Germany.
authors.forename: Ruth
authors.initials: R
authors.lastname: Esser
authors.affiliation: Institute for Cellular therapeutics; IFB-Tx; Hannover Medical School ; Hannover, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Glienke
authors.affiliation: Department of Oral; Cranio-Maxillofacial and Facial Plastic Surgery; Klinikum Hanau GmbH ; Hanau, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Seitz
authors.affiliation: Institute for Cellular therapeutics; IFB-Tx; Hannover Medical School ; Hannover, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Köhl
keywords: HNSCC; NK cell cytotoxicity; NKG2D; TGFβ1; soluble MICA; tumor immune escape mechanisms