Sustained activation and tumor targeting of NKT cells using a CD1d–anti-HER2–scFv fusion protein induce antitumor effects in mice

Stirnemann, Kathrin; Romero, Jacqueline; Baldi, Lucia; Robert, Bruno; Cesson, Valérie; Besra, Gurdyal S.; Zauderer, Maurice; Wurm, Florian Μ.; Corradin, Giampietro; Mach, Jean‐Pierre; MacDonald, H. Robson; Donda, Alena

doi:10.1172/jci33249

Cited by 48 publications

(83 citation statements)

References 46 publications

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“…Several studies have shown improved antitumor activity of iNKT cells with the use of various tools or materials (24,25). In our study, ␣GC-mediated antitumor effect was significantly increased by administration of anti-PD-1 mAb at the time of ␣GC treatment.…”

Section: Resultssupporting

confidence: 47%

Cutting Edge: Programmed Death-1/Programmed Death Ligand 1 Interaction Regulates the Induction and Maintenance of Invariant NKT Cell Anergy

Chang

Kim

et al. 2008

The Journal of Immunology

138

143

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Invariant NKT (iNKT) cells are a distinct subset of T lymphocytes that recognize glycolipid Ags. Upon TCR stimulation, iNKT cells promptly secrete a wide range of cytokines and therefore have been investigated as a target for immunotherapy. However, after primary activation, iNKT cells become hyporesponsive toward their ligand (anergy). The further mechanism behind iNKT cell anergy is poorly understood. We found that a low level of programmed death-1 (PD-1) was constitutively expressed on iNKT cells and that PD-1 expression was increased after stimulation and lasted at least 2 mo. Moreover, not only did blocking of the PD-1/PD ligand 1 (PD-L1) pathway prevent the induction of anergy in iNKT cells, but anergic iNKT cells also recovered responsiveness and these "rescued" cells efficiently mediated antitumor immunity. Our findings suggest that the PD-1/ PD-L1 interaction is essential for the induction and maintenance of iNKT cell anergy. The Journal of Immunology, 2008, 181: 6707-6710. N atural killer T (NKT)3 cells are a distinctive population of T lymphocytes that can recognize glycolipids presented by CD1d, an MHC class I like-molecule (1). A major subset of NKT cells, called type I NKT cells or invariant NKT (iNKT) cells, express an invariant TCR composed of V␣14-J␣18 chains in mice (V␣24-J␣18 in humans). Upon TCR stimulation with a ligand such as ␣-galactosylceramide (␣GC), iNKT cells rapidly produce a wide range of cytokines including IL-4, IFN-␥, and IL-12 (1, 2). This response enables iNKT cells to enhance or regulate the activity of various immune cells in innate and acquired immunity (3). These immunomodulatory roles of iNKT cells are found in diverse diseases, promoting tumor rejection or regulating autoimmune disorders (4 -6).Another unique feature of iNKT cells is that they become unresponsive after stimulation with their ligands. For instance, iNKT cells that have been stimulated with ␣GC have reduced proliferation and cytokine production upon secondary stimulation with the same ligand (7,8). This iNKT cell anergy is a major obstacle in immunotherapeutic trials targeting iNKT cells; however, the mechanism behind the anergy is not clear. A classic concept of anergy in conventional T cells is that the cells become anergic when they receive a TCR signal with insufficient costimulatory signals. In contrast, it has recently been suggested that coinhibitory molecules may actively anergize or tolerize T cells by delivering inhibitory signals into TCR-stimulated T cells (9). Moreover, in cases of chronic viral infection, blockade of the programmed death-1 (PD-1) signal can reverse the anergic phenotype of CD8 T cells (10, 11).PD-1 is well known as a coinhibitory molecule on T cells. In conventional T cells, it is not expressed on naive T cells but is inducibly expressed after T cell activation. The interactions of PD-1 with the PD ligands (PD-L1 and PD-L2) can transduce inhibitory or costimulatory signals into the T cells (12). It is well established that PD-1 plays a critical role in the regulation of immune...

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Section: Resultssupporting

confidence: 47%

Cutting Edge: Programmed Death-1/Programmed Death Ligand 1 Interaction Regulates the Induction and Maintenance of Invariant NKT Cell Anergy

Chang

Kim

et al. 2008

The Journal of Immunology

138

143

View full text Add to dashboard Cite

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“…Furthermore, as repeated i.v. administration of a-GalCer induces iNKT cell anergy and repeated administration of CD1d-targeted constructs results in sustained iNKT cell activation (29), tumor-targeting of iNKT cells or a-GalCer-pulsed APC might alternatively constitute a powerful yet unexplored clinical approach (5).…”

Section: Discussionmentioning

confidence: 99%

CD1d-Restricted Antigen Presentation by Vγ9Vδ2-T Cells Requires Trogocytosis

Schneiders¹,

Prodöhl²,

Ruben³

et al. 2014

Cancer Immunology Research

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CD1d-restricted invariant natural killer T cells (iNKT) constitute an important immunoregulatory T-cell subset that can be activated by the synthetic glycolipid a-galactosylceramide (a-GalCer) and play a dominant role in antitumor immunity. Clinical trials with a-GalCer-pulsed monocyte-derived dendritic cells (moDC) have shown anecdotal antitumor activity in advanced cancer. It was reported that phosphoantigen (pAg)-activated Vg9Vd2-T cells can acquire characteristics of professional antigen-presenting cells (APC). Considering the clinical immunotherapeutic applications, Vg9Vd2-T APC can offer important advantages over moDC, potentially constituting an attractive novel APC platform. Here, we demonstrate that Vg9Vd2-T APC can present antigens to iNKT. However, this does not result from de novo synthesis of CD1d by Vg9Vd2-T, but critically depends on trogocytosis of CD1d-containing membrane fragments from pAg-expressing cells. CD1d-expressing Vg9Vd2-T cells were able to activate iNKT in a CD1d-restricted and a-GalCer-dependent fashion. Although a-GalCerloaded moDC outperformed Vg9Vd2-T APC on a per cell basis, Vg9Vd2-T APC possess unique features with respect to clinical immunotherapeutic application that make them an interesting platform for consideration in future clinical trials. Cancer Immunol Res; 2(8); 732-40. Ó2014 AACR.

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“…iNKT cells bridge the innate and adaptive arms of the immune system by producing a variety of cytokines very rapidly after stimulation (1,2). In view of their transactivating properties, iNKT cells have been implicated in autoimmunity, viral infection, and tumor immunity (1,4,5). During thymic development, iNKT cells are branched off from conventional T cells at double-positive (DP) stage (6).…”

Section: N Atural Killer T Cells Have Been Well Defined As a Uniquementioning

confidence: 99%

Mammalian Target of Rapamycin Complex 1 Orchestrates Invariant NKT Cell Differentiation and Effector Function

Zhang

Tschumi

Corgnac

et al. 2014

The Journal of Immunology

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Invariant NKT (iNKT) cells play critical roles in bridging innate and adaptive immunity. The Raptor containing mTOR complex 1 (mTORC1) has been well documented to control peripheral CD4 or CD8 T cell effector or memory differentiation. However, the role of mTORC1 in iNKT cell development and function remains largely unknown. By using mice with T cell–restricted deletion of Raptor, we show that mTORC1 is selectively required for iNKT but not for conventional T cell development. Indeed, Raptor-deficient iNKT cells are mostly blocked at thymic stage 1–2, resulting in a dramatic decrease of terminal differentiation into stage 3 and severe reduction of peripheral iNKT cells. Moreover, residual iNKT cells in Raptor knockout mice are impaired in their rapid cytokine production upon αGalcer challenge. Bone marrow chimera studies demonstrate that mTORC1 controls iNKT differentiation in a cell-intrinsic manner. Collectively, our data provide the genetic evidence that iNKT cell development and effector functions are under the control of mTORC1 signaling.

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Sustained activation and tumor targeting of NKT cells using a CD1d–anti-HER2–scFv fusion protein induce antitumor effects in mice

Cited by 48 publications

References 46 publications

Cutting Edge: Programmed Death-1/Programmed Death Ligand 1 Interaction Regulates the Induction and Maintenance of Invariant NKT Cell Anergy

Cutting Edge: Programmed Death-1/Programmed Death Ligand 1 Interaction Regulates the Induction and Maintenance of Invariant NKT Cell Anergy

CD1d-Restricted Antigen Presentation by Vγ9Vδ2-T Cells Requires Trogocytosis

Mammalian Target of Rapamycin Complex 1 Orchestrates Invariant NKT Cell Differentiation and Effector Function

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