Cetuximab reconstitutes proinflammatory cytokine secretions and tumour-infiltrating capabilities of sMICA-inhibited NK cells in HNSCC tumour spheroids.
Immunosuppressive factors, such as soluble major histocompatibility complex class I chain-related peptide A (sMICA) and transforming growth factor beta 1 (TGF-beta1), are involved in tumour immune escape mechanisms (TIEMs) exhibited by head and neck squamous cell carcinomas (HNSCCs) and may represen...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2015-11-01
|
| Series: | Frontiers in Immunology |
| Subjects: | |
| Online Access: | http://journal.frontiersin.org/Journal/10.3389/fimmu.2015.00543/full |
| _version_ | 1818548341548515328 |
|---|---|
| author | Stephan eKloess Nicole eChambron Tanja eGardlowski Sandra eWeil Joachim eKoch Ruth eEsser Elke ePogge-von-Strandmann Michael A. Morgan Lubomir eArseniev Oliver eSeitz Ulrike eKoehl |
| author_facet | Stephan eKloess Nicole eChambron Tanja eGardlowski Sandra eWeil Joachim eKoch Ruth eEsser Elke ePogge-von-Strandmann Michael A. Morgan Lubomir eArseniev Oliver eSeitz Ulrike eKoehl |
| author_sort | Stephan eKloess |
| collection | DOAJ |
| description | Immunosuppressive factors, such as soluble major histocompatibility complex class I chain-related peptide A (sMICA) and transforming growth factor beta 1 (TGF-beta1), are involved in tumour immune escape mechanisms (TIEMs) exhibited by head and neck squamous cell carcinomas (HNSCCs) and may represent opportunities for therapeutic intervention. In order to overcome TIEMs, we investigated the antibody-dependent cellular cytotoxicity (ADCC), cytokine release and retargeted tumour-infiltration of sMICA-inhibited patient NK cells expressing Fcγ receptor IIIa (FcγRIIIa, CD16a) in the presence of cetuximab, an anti-EGFR (epidermal growth factor receptor, HER1) monoclonal antibody (mAb). Compared to healthy controls, relapsed HNSCC patients (n = 5) not currently in treatment revealed decreased levels of circulating regulatory NK cell subsets in relation to increased cytotoxic NK cell subpopulations. Elevated sMICA and TGF-beta1 plasma levels correlated with diminished TNFalpha and IFN-gamma release and decreased NKG2D (natural killer group 2 member D)-dependent killing of HNSCC cells by NK cells. Incubation of IL-2-activated patient NK cells with patient plasma containing elevated sMICA or sMICA analogues (shed MICA [shMICA], recombinant MICA [rMICA]) significantly impaired NKG2D-mediated killing by down-regulation of NKG2D surface expression. Of note, CD16 surface expression levels, pro-apoptotic and activation markers, and viability of patient and healthy donor NK cell subpopulations were not affected by this treatment. Accordingly, cetuximab restored killing activity of sMICA-inhibited patient NK cells against cetuximab-coated primary HNSCC cells via ADCC in a dose-dependent manner. Rapid reconstitution of anti-tumour recognition and enhanced tumour-infiltration of treated NK cells was monitored by 24 h co-incubation of HNSCC tumour spheroids with cetuximab (1 µg/ml) and was characterised by increased IFN-gamma and TNFalpha secretion. This data show that the impaired NK cell-dependent tumour-surveillance in relapsed HNSCC patients could be reversed by the re-establishment of ADCC-mediated effector cell activity, thus supporting NK cell-based immunotherapy in combination with antineoplastic monoclonal mAbs. |
| first_indexed | 2024-12-12T08:18:39Z |
| format | Article |
| id | doaj.art-ebef4d50b4cb41a39ab1f1ef4ef58fb8 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-12T08:18:39Z |
| publishDate | 2015-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-ebef4d50b4cb41a39ab1f1ef4ef58fb82022-12-22T00:31:29ZengFrontiers Media S.A.Frontiers in Immunology1664-32242015-11-01610.3389/fimmu.2015.00543160912Cetuximab reconstitutes proinflammatory cytokine secretions and tumour-infiltrating capabilities of sMICA-inhibited NK cells in HNSCC tumour spheroids.Stephan eKloess0Nicole eChambron1Tanja eGardlowski2Sandra eWeil3Joachim eKoch4Ruth eEsser5Elke ePogge-von-Strandmann6Michael A. Morgan7Lubomir eArseniev8Oliver eSeitz9Ulrike eKoehl10Hannover Medical School (MHH)Klinikum Hanau GmbHHannover Medical School (MHH)Georg-Spever-HausGeorg-Spever-HausHannover Medical School (MHH)Universitätsklinikum Köln , Uniklinik Köln, GermanyHannover Medical SchoolHannover Medical School (MHH)Klinikum Hanau GmbHHannover Medical School (MHH)Immunosuppressive factors, such as soluble major histocompatibility complex class I chain-related peptide A (sMICA) and transforming growth factor beta 1 (TGF-beta1), are involved in tumour immune escape mechanisms (TIEMs) exhibited by head and neck squamous cell carcinomas (HNSCCs) and may represent opportunities for therapeutic intervention. In order to overcome TIEMs, we investigated the antibody-dependent cellular cytotoxicity (ADCC), cytokine release and retargeted tumour-infiltration of sMICA-inhibited patient NK cells expressing Fcγ receptor IIIa (FcγRIIIa, CD16a) in the presence of cetuximab, an anti-EGFR (epidermal growth factor receptor, HER1) monoclonal antibody (mAb). Compared to healthy controls, relapsed HNSCC patients (n = 5) not currently in treatment revealed decreased levels of circulating regulatory NK cell subsets in relation to increased cytotoxic NK cell subpopulations. Elevated sMICA and TGF-beta1 plasma levels correlated with diminished TNFalpha and IFN-gamma release and decreased NKG2D (natural killer group 2 member D)-dependent killing of HNSCC cells by NK cells. Incubation of IL-2-activated patient NK cells with patient plasma containing elevated sMICA or sMICA analogues (shed MICA [shMICA], recombinant MICA [rMICA]) significantly impaired NKG2D-mediated killing by down-regulation of NKG2D surface expression. Of note, CD16 surface expression levels, pro-apoptotic and activation markers, and viability of patient and healthy donor NK cell subpopulations were not affected by this treatment. Accordingly, cetuximab restored killing activity of sMICA-inhibited patient NK cells against cetuximab-coated primary HNSCC cells via ADCC in a dose-dependent manner. Rapid reconstitution of anti-tumour recognition and enhanced tumour-infiltration of treated NK cells was monitored by 24 h co-incubation of HNSCC tumour spheroids with cetuximab (1 µg/ml) and was characterised by increased IFN-gamma and TNFalpha secretion. This data show that the impaired NK cell-dependent tumour-surveillance in relapsed HNSCC patients could be reversed by the re-establishment of ADCC-mediated effector cell activity, thus supporting NK cell-based immunotherapy in combination with antineoplastic monoclonal mAbs.http://journal.frontiersin.org/Journal/10.3389/fimmu.2015.00543/fullADCCTGF-betaSoluble MICAcetuximab-activated NK cellsHNSCC tumour spheroidsTumour infiltrations |
| spellingShingle | Stephan eKloess Nicole eChambron Tanja eGardlowski Sandra eWeil Joachim eKoch Ruth eEsser Elke ePogge-von-Strandmann Michael A. Morgan Lubomir eArseniev Oliver eSeitz Ulrike eKoehl Cetuximab reconstitutes proinflammatory cytokine secretions and tumour-infiltrating capabilities of sMICA-inhibited NK cells in HNSCC tumour spheroids. Frontiers in Immunology ADCC TGF-beta Soluble MICA cetuximab-activated NK cells HNSCC tumour spheroids Tumour infiltrations |
| title | Cetuximab reconstitutes proinflammatory cytokine secretions and tumour-infiltrating capabilities of sMICA-inhibited NK cells in HNSCC tumour spheroids. |
| title_full | Cetuximab reconstitutes proinflammatory cytokine secretions and tumour-infiltrating capabilities of sMICA-inhibited NK cells in HNSCC tumour spheroids. |
| title_fullStr | Cetuximab reconstitutes proinflammatory cytokine secretions and tumour-infiltrating capabilities of sMICA-inhibited NK cells in HNSCC tumour spheroids. |
| title_full_unstemmed | Cetuximab reconstitutes proinflammatory cytokine secretions and tumour-infiltrating capabilities of sMICA-inhibited NK cells in HNSCC tumour spheroids. |
| title_short | Cetuximab reconstitutes proinflammatory cytokine secretions and tumour-infiltrating capabilities of sMICA-inhibited NK cells in HNSCC tumour spheroids. |
| title_sort | cetuximab reconstitutes proinflammatory cytokine secretions and tumour infiltrating capabilities of smica inhibited nk cells in hnscc tumour spheroids |
| topic | ADCC TGF-beta Soluble MICA cetuximab-activated NK cells HNSCC tumour spheroids Tumour infiltrations |
| url | http://journal.frontiersin.org/Journal/10.3389/fimmu.2015.00543/full |
| work_keys_str_mv | AT stephanekloess cetuximabreconstitutesproinflammatorycytokinesecretionsandtumourinfiltratingcapabilitiesofsmicainhibitednkcellsinhnscctumourspheroids AT nicoleechambron cetuximabreconstitutesproinflammatorycytokinesecretionsandtumourinfiltratingcapabilitiesofsmicainhibitednkcellsinhnscctumourspheroids AT tanjaegardlowski cetuximabreconstitutesproinflammatorycytokinesecretionsandtumourinfiltratingcapabilitiesofsmicainhibitednkcellsinhnscctumourspheroids AT sandraeweil cetuximabreconstitutesproinflammatorycytokinesecretionsandtumourinfiltratingcapabilitiesofsmicainhibitednkcellsinhnscctumourspheroids AT joachimekoch cetuximabreconstitutesproinflammatorycytokinesecretionsandtumourinfiltratingcapabilitiesofsmicainhibitednkcellsinhnscctumourspheroids AT rutheesser cetuximabreconstitutesproinflammatorycytokinesecretionsandtumourinfiltratingcapabilitiesofsmicainhibitednkcellsinhnscctumourspheroids AT elkeepoggevonstrandmann cetuximabreconstitutesproinflammatorycytokinesecretionsandtumourinfiltratingcapabilitiesofsmicainhibitednkcellsinhnscctumourspheroids AT michaelamorgan cetuximabreconstitutesproinflammatorycytokinesecretionsandtumourinfiltratingcapabilitiesofsmicainhibitednkcellsinhnscctumourspheroids AT lubomirearseniev cetuximabreconstitutesproinflammatorycytokinesecretionsandtumourinfiltratingcapabilitiesofsmicainhibitednkcellsinhnscctumourspheroids AT olivereseitz cetuximabreconstitutesproinflammatorycytokinesecretionsandtumourinfiltratingcapabilitiesofsmicainhibitednkcellsinhnscctumourspheroids AT ulrikeekoehl cetuximabreconstitutesproinflammatorycytokinesecretionsandtumourinfiltratingcapabilitiesofsmicainhibitednkcellsinhnscctumourspheroids |