IL‐2‐activated haploidentical NK cells restore NKG2D‐mediated NK‐cell cytotoxicity in neuroblastoma patients by scavenging of plasma MICA

Abstract

NK group 2D (NKG2D)-expressing NK cells exhibit cytolytic activity against various tumors after recognition of the cellular ligand MHC class I chain-related gene A (MICA). However, release of soluble MICA (sMICA) compromises NKG2D-dependent NK-cell cytotoxicity leading to tumor escape from immunosurveillance. Although some molecular details of the NKG2D-MICA interaction have been elucidated, its impact for donor NK (dNK) cellbased therapy of solid tumors has not been studied. Within an ongoing phase I/II trial, we used allogeneic IL-2 activated dNK cells after haploidentical stem cell transplantation for immunotherapy of patients with high-risk stage IV neuroblastoma. NKG2D levels on activated dNK cells increased strongly when compared with freshly isolated dNK cells and correlated with enhanced NK-cell cytotoxicity. Most importantly, elevated sMICA levels in patients plasma correlated significantly with impaired dNK-cell-mediated cytotoxicity. This effect could be reversed by high-dose infusion of activated dNK cells, which display high levels of surface NKG2D. Our data suggest that the provided excess of NKG2D leads to clearance of sMICA and preserves cytotoxicity of dNK cells via non-occupied NKG2D. In conclusion, our results identify this tumor immune escape mechanism as a target to improve immunotherapy of neuroblastoma and presumably other tumors.

Increased sMICA and TGFβ 1 levels in HNSCC patients impair NKG2D-dependent functionality of activated NK cells

“…High sMICA levels coincided also with decreased survival rates in HNSCC patients potentially synergizing with high sMICB levels. 14,34 Although sMICA appears to be a trend-setting for TIEMs of neuroblastoma 17,20 and HNSCC (CURRENT STUDY) the precise contribution of individual NKG2D ligands to TIEMs has not been evaluated yet. However, the plasma levels of the different NKG2D ligands vary considerably among patients and tumor entities.…”

“…11,[17][18][19] Interestingly, we demonstrated that sMICA and transforming growth factor b 1 (TGFb 1 ) compromise the function of activated donor NK cells applied as an immunotherapeutic approach in children with neuroblastoma after haploidentical stem cell transplantation (HSCT). 20 Thus sMICA/TGFb 1 play a critical role in the immune surveillance and effector cell-mediated killing of tumor cells with respect to both patient and donor NK cells.…”

Natural killer cell-based adoptive immunotherapy eradicates and drives differentiation of chemoresistant bladder cancer stem-like cells

“…Marked levels of the soluble form of the MHC class I-related chain A, identified as a human NKG2D ligand, were found in the sera of patients with disseminated head-and-neck squamous cell [26] and human hepatocellular carcinomas [27] and neuroblastoma [28]. This tumor-derived soluble inhibitory ligand appears to be responsible for the downregulation of NKG2D expression in NK cells and subsequent impaired NKG2D-mediated cytotoxicity in patients with advanced disease.…”

Pre-emptive immunotherapy with purified natural killer cells after haploidentical SCT: a prospective phase II study in two centers

“…Interestingly, high doses of activated haploidentical NK-DLI could restore NKG2D-mediated cytotoxicity by scavenging of sMICA. 36 Pharmacological upregulation of NKG2D ligands is also being explored as a potential way of rendering blast cells more sensitive to NK cellmediated lysis. 37 Therefore, future studies should also focus on strategies to overcome these tumor immune escape mechanisms.…”