Increased sMICA and TGFβ₁levels in HNSCC patients impair NKG2D-dependent functionality of activated NK cells

Abstract

Abbreviations: ADCC, antigen-dependent cellular cytotoxicity; HNSCC, head-and-neck squamous cell carcinoma; HSCT, haploidentical stem cell transplantation; KIR, killer cell immunoglobulin-like receptor; NCR, natural cytotoxicity receptor; NK, natural killer; NKG2D, natural-killer group 2, member D; vitsMICA/NKG2DL, soluble major histocompatibility complex Class I chain-related peptide A; TGFb1, transforming growth factor beta 1; TIEM, tumor immune escape mechanismDisseminated 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/antiinflammatory cytokines were decreased in HNSCC patients, while soluble major histocompatibility complex Class I chain-related peptide A (sMICA) and transforming growth factor b 1 (TGFb 1 ) plasma levels were markedly elevated. Increased sMICA and TGFb 1 concentrations 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 TGFb 1 markedly impaired NKG2D-dependent cytotoxicity against HNSCC cells upon incubation with patient-derived and IL-2 activated NK cells vs. 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-vitro blocking and neutralization experiments demonstrated a synergistic negative impact of sMICA and TGFb 1 on 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 TGFb 1 , indicates timely depletion of these immunosuppressing molecules may promote NK cell-based immunotherapy.

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

“…Previously, we could show a correlation of high sMICA plasma levels and impaired NK cell cytotoxicity in patients with HNSCC (33, 41). Since these studies only investigated sMICA in NKG2D-dependent tumor immune escape, in the current study, we determined the levels of all the shed NKG2DLs (sMICA, sMICB, and sULBP1–3) in plasma samples of 44 HNSCC patients (patients’ characteristics are summarized in Table 1).…”

“…However, shedding of NKG2DLs leads to impaired cytotoxicity of NK cells and T cells due to loss of antigenic NKG2DLs and shed NKG2DL (sNKG2DL)-induced downregulation of NKG2D (24–26). Consequently, patients suffering from various cancers (27–33) demonstrated an inverse correlation of sMICA plasma levels and NKG2D-dependent NK cell cytotoxicity. Since all sNKG2DLs engage with a common receptor, the cumulative level of all sNKG2DLs is decisive for their biological/clinical effect.…”

Human CD56bright NK Cells: An Update

“…However, they reported an increase in cellular apoptosis that was restricted to the circulating CD56 dim population (22). The reduced percentage of circulating CD56 bright cells was confirmed in head and neck cancer patients by two additional distinct studies (23,24). In contrast, Mamessier et al (25) observed that the amount of circulating CD56 bright NK cells in BC patients increased in relation to the grade of malignancy.…”

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.…”