Sustained expansion of NKT cells and antigen-specific T cells after injection of α-galactosyl-ceramide loaded mature dendritic cells in cancer patients

Chang, D.; Osman, Keren; Connolly, John F.; Kukreja, Anjli; Krasovsky, Joseph; Pack, Maggi; Hutchinson, Aisha; Geller, Matthew D.; Liu, Naian; Annable, Rebecca; Shay, Jennifer M.; Kirchhoff, Kelly; Nishi, Nobusuke; Ando, Yumiko; Hayashi, Kyozo; Hassoun, Hani; Steinman, Ralph M.; Dhodapkar, Madhav V.

doi:10.1084/jem.20042592082307c

Cited by 79 publications

(120 citation statements)

References 0 publications

Supporting

Mentioning

116

Contrasting

Order By: Relevance

“…patients with various cancers [39], adult and pediatric acute versus chronic asthmatics, untreated or on various treatments [40][41][42][43][44][45]) and their various tissues, as well as intervening therapeutically. Given that several approaches to exploit iNKT cells have entered clinical trials [46,47], development of such a selective reagent seems timely. …”

Section: Discussionmentioning

confidence: 99%

“…(A) Histograms of Va24, Vb11, and 6B11 expression as determined for a TCR-negative Jurkat cell subline transfected to transiently express iNKT Va24Ja18 and Vb11 TCR, as previously described for other CD1-reactive T cells [31]. (B) Liver mononuclear cells from human invariant Va24Ja18 transgenic mice [46] or C57BL/6 wild-type mice were specifically stained with 6B11-biotin or Va24-biotin and fluorescent streptavidin and otherwise with mouse-specific directly conjugated mAb as shown. Note that 6B11 identified high-and low-level expressing transgenic iNKT, whereas Va24 was uniformly positive.…”

Section: B11 Is Highly Specific For Inkt Subsets In Pbmcmentioning

confidence: 99%

“…This may reflect 6B11 having different affinity for Va24Ja18 with distinct murine Vb pairings. (C-H) Splenic sections from human Va24Ja18 transgenic [46] or C57BL/6 wild-type mice were double-stained with 6B11 and mouse anti-CD3 antibody or isotype controls. Only the human iNKT transgenic spleens contained 6B11-reactive T cells.…”

Section: B11 Is Highly Specific For Inkt Subsets In Pbmcmentioning

confidence: 99%

See 2 more Smart Citations

Selective activation, expansion, and monitoring of human iNKT cells with a monoclonal antibody specific for the TCR α‐chain CDR3 loop

Exley¹,

Hou²,

Shaulov³

et al. 2008

Eur J Immunol

View full text Add to dashboard Cite

A significant fraction of CD1d-restricted T cells express an invariant T cell receptor (TCR) a-chain. These highly conserved invariant NKT (iNKT) populations are important regulators of a wide spectrum of immune responses. The ability to directly identify and manipulate iNKT cells is essential to understanding their function and to exploit their therapeutic potential. To this end, we sought monoclonal and polyclonal antibodies specific for iNKT cells by immunizing CD1d KO mice, which lack iNKT cells, with a cyclic peptide modeled after the TCRa CDR3 loop. One mAb (6B11) was specific for cloned and primary human but not rodent iNKT cells and the human invariant TCRa, as shown by transfection and reactivity with human invariant TCRa transgenic T cells ex vivo and in situ. 6B11 was utilized to identify, purify, and expand iNKT cells from an otherwise minor component of human peripheral blood lymphocytes and to specifically identify human iNKT cells in tissue. Thus, we report a novel and general strategy for the generation of mAb specific for the CDR3 loop encoded by the TCR of interest. Specifically, an anti-Va24Ja18 CDR3 loop clonotypic TCR mAb is available for the enumeration and therapeutic manipulation of human and non-human primate iNKT populations.Key words: Anti-TCR Á Clonotypic Á Cyclic peptide Á IL-4 Á Invariant NKT Introduction Natural killer T (NKT) cells expressing surface markers found on NK cells (e.g. CD161, CD56, CD94 and/or KIR) comprise up to 20% of human peripheral blood lymphocytes (PBL) [1], whilst only *0.05% of PBL are CD1d restricted [2][3][4]. A major proportion of such PBL CD1d-reactive T cells are invariant NKT (iNKT) cells in that they express an invariant TCR a-chain, Va24Ja18 in humans and Va24Ja18 in mice [3,5,6]. Both human and murine iNKT cells can be activated in a CD1d-dependent fashion by the synthetic glycolipid a-galactosylceramide (a-GalCer) and self-or pathogen-derived glycolipid molecules [7][8][9]. Activation of iNKT cells leads to rapid production of large amounts of numerous cytokines and consequent stimulation of Mark A. Exley et al. Eur. J. Immunol. 2008. 38: 1756-1766 [3,[10][11][12][13][14], perhaps most significantly by regulating dendritic cell (DC) function [10,15]. The frequency and functional activity of iNKT cells have been shown to be important determinants for the progression of autoimmune disorders, tumors, and viral infections [10,[16][17][18]. In humans, a reduction in the number of circulating iNKT cells is accompanied by a striking Th1 polarization in certain autoimmune diseases such as type 1 diabetes, systemic sclerosis and rheumatoid arthritis [18][19][20][21]. Cancer patients have decreased numbers of iNKT cells in their blood and impaired in vitro proliferative potential, reversible with IL-2 [22][23][24]. As well as the reduced numbers of these cells found in many cancer patients, there is a striking reversal of cytokine polarization relative to that found in diabetes, which may reflect a reduction in iNKT anti-tumor activity during progression [...

show abstract

Section: Discussionmentioning

confidence: 99%

Section: B11 Is Highly Specific For Inkt Subsets In Pbmcmentioning

confidence: 99%

Section: B11 Is Highly Specific For Inkt Subsets In Pbmcmentioning

confidence: 99%

See 1 more Smart Citation

Selective activation, expansion, and monitoring of human iNKT cells with a monoclonal antibody specific for the TCR α‐chain CDR3 loop

Exley¹,

Hou²,

Shaulov³

et al. 2008

Eur J Immunol

View full text Add to dashboard Cite

show abstract

“…Numerical and functional iNKT cell deficiencies have been reported in a number of human diseases [189][190][191][192]. These findings led to clinical trials in humans for cancer involving the adoptive transfer of ex vivo expanded autologous DC, pulsed with a-GC, in the absence or presence of expanded iNKT cells [193][194][195]. Although these treatments were well-tolerated and resulted in the generation of antitumor CD4 + and CD8 + T cell responses, clinical responses have been limited and future refinements are required to optimize the generation of efficient antitumor immunity.…”

Section: Other Unconventional T Cells Bridging Innate and Adaptive Immentioning

confidence: 99%

“…Even more, other unconventional T cell subsets may drive similar reactions, albeit in response to different stimuli and in different anatomical contexts, arguing for a general role of innate T cell subsets as natural adjuvants to promote protective immune responses. In analogy to the exploitation of iNKT cells in the clinic [193][194][195]223,224], approaches specifically targeting Vc9/Vd2 T cells may have a similar potential as vaccine adjuvant, to boost immune responses against pathogens and tumors and to modulate autoimmune responses.…”

Section: Innate Regulation Of Adaptive Immune Responses: Vd2 + Versusmentioning

confidence: 99%

Human Vγ9/Vδ2 T cells: Innate adaptors of the immune system

Tyler

Doherty

Moser

et al. 2015

Cellular Immunology

View full text Add to dashboard Cite

a b s t r a c tUnconventional T cells are gaining center stage as important effector and regulatory cells that orchestrate innate and adaptive immune responses. Human Vc9/Vd2 T cells are amongst the best understood unconventional T cells, as they are easily accessible in peripheral blood, can readily be expanded and manipulated in vitro, respond to microbial infections in vivo and can be exploited for novel tumor immunotherapies. We here review findings that suggest that Vc9/Vd2 T cells, and possibly other unconventional human T cells, play an important role in bridging innate and adaptive immunity by promoting the activation and differentiation of various types of antigen-presenting cells (APCs) and even turning into APCs themselves, and thereby pave the way for antigen-specific effector responses and long-term immunological memory. Although the direct physiological relevance for most of these mechanisms still needs to be demonstrated in vivo, these findings may have implications for novel therapies, diagnostic tests and vaccines.Ó 2015 Published by Elsevier Inc. Introduction cd T cells represent a third lineage of lymphocytes expressingre-arranged antigen receptors that co-evolved with 'classical' B cells and ab T cells over 400 million years, arguing for a crucial and non-redundant contribution of each lymphocyte to effective immune responses, and hence the evolutionary survival of all jawed vertebrate species [1]. 30 years have passed since the accidental and unexpected cloning of the cd T cell receptor (TCR) and the subsequent realization that ab T cells and cd T cells are fundamentally different with respect to the types of antigens they recognize and the distinct effector functions triggered upon such recognition. However, the manifold contributions of cd T cells to homeostasis, inflammation, infection and tumor surveillance have historically been neglected and are only beginning to be integrated into comprehensive models of the immune system [1][2][3][4][5][6][7].1. Innate-like pattern recognition by human Vc9/Vd2 T cells Like other 'unconventional' T cells carrying an ab TCR such as mucosal-associated invariant T (MAIT) cells and natural killer T (NKT) cells, cd T cells are characterized by a markedly restrictedTCR usage that allows them to recognize self and non-self molecules in the absence of classical antigen presentation via MHC I or MHC II. Vc9/Vd2 + cd T cells represent the major cd T cell subset in human peripheral blood where they typically comprise 1-5% in healthy adults [8]. In many microbial infections, Vc9/Vd2 T cells increase locally and/or systemically [9,10] and can reach in excess of 50% of all peripheral T cells within a matter of days [11], revealing a fundamental role of this unconventional T cell population in acute disease and suggesting their exploitation for diagnostic and therapeutic purposes [12][13][14]. Vc9/Vd2 T cells uniformly respond to a class of low molecular weight molecules often referred to as 'phosphoantigens' that represent metabolites of the isoprenoid biosynthesis...

show abstract

Therapy for minimal residual tumor disease: β‐Galactosylceramide inhibits the growth of recurrent HPV16‐associated neoplasms after surgery and chemotherapy

Šímová

Indrová

Bieblová

et al. 2010

Intl Journal of Cancer

View full text Add to dashboard Cite

Natural killer T (NKT) cells are potent modulators of antitumor immunity. Their protective effects can be achieved upon their activation by glycolipid ligands presented in the context of the CD1d molecule. These CD1d-binding glycolipid antigens have been described as potent therapeutic agents against tumors, infections, as well as autoimmune diseases. Immunoregulatory and therapeutic effects of glycolipid ligands depend on their structure and modes of administration. Therefore, more studies are needed for optimization of the particular therapeutic settings. This study was focused on the tumor-inhibitory effects of 12 carbon acyl chain b-galactosyl ceramide (C12 b-D-Galactosyl Ceramide; b-GalCer(C12)) on the growth of human papillomavirus type 16 (HPV16)-associated neoplasms transplanted in syngeneic mice. Treatment of tumor-bearing mice with b-GalCer(C12) 3-14 days after tumor cell transplantation significantly inhibited the growth of the major histocompatability complex (MHC) Class I-positive (TC-1), as well as MHC Class I-deficient (TC-1/A9) HPV16-asssociated tumors. Moreover, administration of b-GalCer(C12) after surgical removal of TC-1 tumors inhibited the growth of tumor recurrences. Similar results were obtained in the treatment of tumors after chemotherapy. b-GalCer(C12) treatment turned out to be also synergistic with immunotherapy based on administration of IL-12-producing cellular vaccines. These results suggest that bGalCer(C12), whose antitumor effects have so far not been studied in detail, can be effective for the treatment of minimal residual tumor disease as well as an adjuvant for cancer immunotherapy.Natural killer T (NKT) cells characterized by cell surface expression of T-cell and NK-cell receptors are important immune regulators that can either promote or suppress antitumor and anti-infection immunity, as well as autoimmunity.1-3 Antitumor activities of NKT cells have mainly been attributed to their Type I (expressing Va14Ja18 and Va24Ja18 TCRa in mice and humans, respectively) that recognize glycolipid antigens in the context of major histocompatability complex (MHC) Class I-like molecule CD1d. NKT cells can be modulated by analogues of their natural, so far poorly characterized, glycolipid ligands. Their specific effects, e.g. induction of cytokine production, NKT cell expansion and activation of a variety of immune cells, as well as NKT cell receptor downregulation and induction of NKT cell anergy strongly depend on their structure and mode of administration. 4,5 So far, most in vivo studies investigating antitumor potential of NKT cell-activating glycolipids have been focused on a-galactosylceramide, originally described as an antitumor drug.6 Much less is known about the antitumor effects of b-anomers. Several clinical studies were performed in which the patients were given either free a-galactosylceramide (a-GalCer) or dendritic cells pulsed with a-GalCer.7-9 In these trials, NKT cell activation/expansion and cytokine production was observed in the treated patients. However, the immun...

show abstract

Sustained expansion of NKT cells and antigen-specific T cells after injection of α-galactosyl-ceramide loaded mature dendritic cells in cancer patients

Cited by 79 publications

References 0 publications

Selective activation, expansion, and monitoring of human iNKT cells with a monoclonal antibody specific for the TCR α‐chain CDR3 loop

Selective activation, expansion, and monitoring of human iNKT cells with a monoclonal antibody specific for the TCR α‐chain CDR3 loop

Human Vγ9/Vδ2 T cells: Innate adaptors of the immune system

Therapy for minimal residual tumor disease: β‐Galactosylceramide inhibits the growth of recurrent HPV16‐associated neoplasms after surgery and chemotherapy

Contact Info

Product

Resources

About