TGF-β Utilizes SMAD3 to Inhibit CD16-Mediated IFN-γ Production and Antibody-Dependent Cellular Cytotoxicity in Human NK Cells

Trotta, Rossana; Col, Jessica Dal; Yu, Jianhua; Ciarlariello, David; Thomas, Brittany; Zhang, Xiaoli; Allard, Jeffrey; Min, Wei; Mao, Hsiaoyin; Byrd, John C.; Perrotti, Danilo; Caligiuri, Michael A.

doi:10.4049/jimmunol.181.6.3784

Cited by 212 publications

(213 citation statements)

References 54 publications

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“…28,29 The expression levels of CD16a on the NK92/CD16a cells did not differ remarkably from those on NK cells in PBMCs isolated from healthy volunteers. For these reasons, the use of NK92/CD16a seemed to be appropriate for evaluating ADCC mediated by cetuximab.…”

Section: Discussionmentioning

confidence: 98%

KRAS mutation confers resistance to antibody‐dependent cellular cytotoxicity of cetuximab against human colorectal cancer cells

Nakadate

Kodera²,

Kitamura³

et al. 2013

Intl Journal of Cancer

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Cetuximab is a chimeric IgG1 monoclonal antibody (mAb) that targets the extracellular domain of epidermal growth factor receptor (EGFR). Oncogenic KRAS mutations in tumors have been shown to be a negative predictor of the response of colorectal cancer (CRC) to cetuximab treatment. Cetuximab exerts its therapeutic effects through several mechanisms including antibody-dependent cellular cytotoxicity (ADCC). However, the influence of KRAS mutations on cetuximab-mediated ADCC is not fully understood. Here, we investigated cetuximab-mediated ADCC in two pairs of isogenic CRC cells with or without a KRAS mutation. Peripheral blood mononuclear cells (PBMCs) from healthy volunteers and NK92, a natural killer (NK) cell line that exogenously expresses FccRIIIa (CD16a), were used as effector cells. In an ADCC assay, perforin-dependent target cell lysis was not affected by the KRAS mutation status. On the other hand, perforin-independent ADCC was observed only in CRC cells with wild-type KRAS, but not in cells with mutant KRAS. Neutralizing experiments revealed that the Fas-Fas ligand (FasL) interaction was responsible for the induction of apoptosis and perforin-independent ADCC. Furthermore, the presence of effector cells clearly enhanced the growth-inhibitory effect of cetuximab only in CRC cells with wild-type KRAS, but not in those with mutant KRAS. These findings suggest that ADCC is an important mode of action of cetuximab and that KRAS mutation impairs the therapeutic effect exerted by cetuximab-mediated ADCC.

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Section: Discussionmentioning

confidence: 98%

KRAS mutation confers resistance to antibody‐dependent cellular cytotoxicity of cetuximab against human colorectal cancer cells

Nakadate

Kodera²,

Kitamura³

et al. 2013

Intl Journal of Cancer

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“…Therefore, TGF-b could contribute to the immune deficit in CLL. In addition, TGF-b inhibits CD16-mediated IFN-g production and ADCC in human NK cells from healthy donors (48). Thus, in vivo administration of rhIL-15 to CLL patients could activate and expand cytotoxic effectors, as well as inhibit the immunosuppressive effects of TGF-b on NK cells.…”

Section: Discussionmentioning

confidence: 99%

Recombinant Human IL-15 Trans-Presentation by B Leukemic Cells from Chronic Lymphocytic Leukemia Induces Autologous NK Cell Proliferation Leading to Improved Anti-CD20 Immunotherapy

Laprévotte

Voisin

Ysebaert

et al. 2013

The Journal of Immunology

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Recombinant human IL-15 (rhIL-15) is one of the most promising cytokines for antitumor immunotherapy. In physiology IL-15 trans-presentation by accessory cells leads to pleiotropic activities, including activation of immune cells, such as NK cells. NK cells are largely involved in Ab-dependent cellular cytotoxicity mediated by therapeutic mAbs, such as rituximab, in chronic lymphocytic leukemia (CLL). Nevertheless, in CLL, Ab-dependent cellular cytotoxicity is relatively impaired by the low E:T ratio (NK/B leukemic cells). Thus, any strategy leading to an increase in NK cell number and activation status can offer new strategies for CLL treatment. To this end, we evaluated the effect of rhIL-15 on autologous NK cell stimulation in CLL samples. We show that rhIL-15 induces NK cell activation and proliferation, leading to improved B leukemic cell depletion. This phenomenon is significantly increased in the presence of anti-CD20 mAbs. In addition, the greater effect of obinutuzumab versus rituximab suggests a cooperative role between rhIL-15 signaling and CD16 signaling in the induction of NK cell proliferation. Moreover, rhIL-15–induced proliferation of autologous NK cells is strictly dependent on their interaction with B leukemic cells, identified in this study as new accessory cells for rhIL-15 trans-presentation. Thus, rhIL-15 is able to promote NK cell–based activity in Ab immunotherapy of CLL.

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“…We did not find a KIR mismatch in graft versus tumor direction in any of the donor-recipient pairs tested. Trotta et al showed the importance of TGF-b on the inhibition of IFN-g production and antibody-dependent cellular cytotoxicity in human NK cells [45].…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2010

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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.

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TGF-β Utilizes SMAD3 to Inhibit CD16-Mediated IFN-γ Production and Antibody-Dependent Cellular Cytotoxicity in Human NK Cells

Cited by 212 publications

References 54 publications

KRAS mutation confers resistance to antibody‐dependent cellular cytotoxicity of cetuximab against human colorectal cancer cells

KRAS mutation confers resistance to antibody‐dependent cellular cytotoxicity of cetuximab against human colorectal cancer cells

Recombinant Human IL-15 Trans-Presentation by B Leukemic Cells from Chronic Lymphocytic Leukemia Induces Autologous NK Cell Proliferation Leading to Improved Anti-CD20 Immunotherapy

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

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