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[Cancer Research 59, 5102-5105, October 15, 1999]
© 1999 American Association for Cancer Research

Advances in Brief

Antitumor Cytotoxicity Mediated by Ligand-activated Human V{alpha}24 NKT Cells1

Tetsu Kawano, Toshinori Nakayama, Noriaki Kamada, Yoshikatsu Kaneko, Michishige Harada, Nobutaka Ogura, Yasunori Akutsu, Shinichiro Motohashi, Toshihiko Iizasa, Hideharu Endo, Takehiko Fujisawa, Hiroshi Shinkai and Masaru Taniguchi2

Core Research for Evolutional Science and Technology Project and Department of Molecular Immunology, Graduate School of Medicine [T. K., T. N., N. K., Y. K., M. H., N. O., Y. A., S. M., M. T.], Department of Dermatology, School of Medicine [N. K., H. E., H. S.], and Department of Surgery, Institute of Pulmonary Cancer Research Center, School of Medicine [S. M., T. I., T. F.], Chiba University, Chiba 260-8670, Japan


   ABSTRACT
Top
 ABSTRACT
Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 
Human V{alpha}24 NKT cells bearing an invariant V{alpha}24J{alpha}Q antigen receptor, the counterpart of the murine V{alpha}14 NKT cells, are activated by the specific ligand, {alpha}-galactosylceramide ({alpha}-GalCer) in a CD1d-dependent manner. Here, we demonstrate that the {alpha}-GalCer-activated V{alpha}24 NKT cells exert a potent perforin-dependent cytotoxic activity against a wide variety of human tumor cell lines. In addition, we demonstrate that V{alpha}24 NKT cells and dendritic cells (DCs) from melanoma patients are functionally normal, even in the tumor-bearing status. The potential use of {alpha}-GalCer-activated V{alpha}24 NKT cells and/or DCs from patients for cancer immunotherapy is discussed.


   Introduction
Top
 ABSTRACT
 Introduction
Materials and Methods
 Results
 Discussion
 REFERENCES
 
The murine V{alpha}14 NKT cells recognize a glycolipid, {alpha}-GalCer,3 in a CD1d-dependent fashion (1 , 2) and display an NK-like cytotoxicity against various tumor cell lines (3) . The activated V{alpha}14 NKT cells are also shown to inhibit tumor metastasis in certain experimental animal models (3) . Human NKT cells bearing the invariant V{alpha}24J{alpha}Q receptor are considered to be the counterpart of murine V{alpha}14 NKT cells and may recognize similar antigens to those of the murine V{alpha}14 NKT cells, because of the striking homology between human V{alpha}24 and mouse V{alpha}14 receptors, particularly in their CDR3 region (4) . In fact, human V{alpha}24 NKT cells have been found to be activated by {alpha}-GalCer in a CD1d-dependent fashion (5, 6, 7) ; thus, it is conceivable that human V{alpha}24 NKT cells could also develop antitumor activity upon {alpha}-GalCer stimulation. Here, we show that V{alpha}24 NKT cells from PBLs of patients with malignant melanoma can be activated by {alpha}-GalCer and display a potent perforin-dependent cytotoxic activity. Also, the ability of DCs to present {alpha}-GalCer is found to be preserved in melanoma patients. These findings raise the possibility that this "{alpha}-GalCer/CD1-NKT cell system" could become a new effective tool for cancer immunotherapy.


   Materials and Methods
Top
 ABSTRACT
 Introduction
 Materials and Methods
Results
 Discussion
 REFERENCES
 
In Vitro Activation and Expansion of V{alpha}24 NKT Cells.
V{alpha}24 NKT cells were purified from umbilical cord blood or PBLs of healthy volunteers and patients with malignant melanomas after obtaining the informed consent (7) . FITC-conjugated anti-V{alpha}24 monoclonal antibody (C15; Coulter-Immunotech, Miami, FL) and anti-FITC magnetic beads (MACS; Miltenyi Biotech, Gladbach, Germany) were used for separation. For the preparation of APCs, CD3- cells (purity >99%) were purified by negative selection by MACS. Enriched V{alpha}24 NKT cells (1 x 105) and CD3- APCs (1 x 106) were cocultured in the presence of {alpha}-GalCer (10 ng/ml; KRN7000, Kirin Brewery Co. Tokyo, Japan) and recombinant human IL-2 (100 units/ml; Boehringer Mannheim, Mannheim, Germany).

Flow Cytometry Analysis.
The percentages of V{alpha}24 NKT cells and the expression levels of MHC class I molecules were evaluated by flow cytometry analysis (7) with specific antibodies as follows; anti-V{alpha}24 (C15); anti-V{beta}11 (C21; Immunotech); anti-CD3 (UCTH-1; PharMingen, La Jolla, CA); and pan-reactive anti-class I antibody (G46–2.6; PharMingen).

Measurement of Cytotoxic Activity of Activated V{alpha}24 NKT Cells against Human Tumor Cell Lines.
Cytotoxicity of {alpha}-GalCer-activated V{alpha}24 NKT cells was measured by a standard 4-h 51Cr-release assay (3) on various human tumor cell lines; Daudi B lymphoma, Molt-4 T lymphoma, and K562 myelogenous leukemia; SK-Mel-28 and HMV-1 malignant melanoma; PC10 squamous cell lung carcinoma, PC6 small cell lung carcinoma, PC13 large cell lung carcinoma, and ABC-1 lung adenocarcinoma; Alexander hepatoma; RCM-1 colon adenocarcinoma; PANC-1 pancreas carcinoma; HeLa uterine cervical carcinoma; SHIN-3 ovarian adenocarcinoma; and TN-1 neuroblastoma. Con A blasts of human PBLs were also used as targets. Treatment of V{alpha}24 NKT cells with concanamycin A (Wako Pure Chemical, Tokyo, Japan) was performed as described (3) .

Evaluation of Antitumor Effects of V{alpha}24 NKT Cells in Vivo.
A human esophageal cancer T.Tn cell line (1 x 107) was inoculated s.c. into the back of BALB/c nude mice (SLC, Shizuoka, Japan) with or without activated V{alpha}24 NKT cells (1 x 107) according to the protocol described by Winn (Ref. 8 ; Winn’s assay). IL-2 (5000 units) was administrated i.p. once a day from days 0 to 4 as described (9, 10, 11) .

Evaluation of the {alpha}-GalCer Presentation of DCs of Melanoma Patients.
Human DCs were prepared from PBLs of melanoma patients. Briefly, plastic-adherent cells of PBLs were cultured in the presence of recombinant human granulocyte/macrophage-colony stimulating factor (800 units/ml; Kirin Brewery Co., Tokyo, Japan) and IL-4 (500 units/ml; Genzyme, Miami, FL) for 4 days. The cultured DCs were then pulsed with {alpha}-GalCer (100 ng/ml) or control vehicle for 12 h. Nonadherent cells were washed extensively, irradiated (5000 rads), and cocultured for 72 h with murine V{alpha}14 NKT cells from RAG-1-/- V{alpha}14tg V{beta}8.2tg mice (3) . The ability of DCs from melanoma patients to present {alpha}-GalCer was evaluated by [3H]thymidine uptake of the murine V{alpha}14 NKT cells.


   Results
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
Discussion
 REFERENCES
 
Evaluation of the in Vitro and in Vivo Cytotoxic Activity of {alpha}-GalCer-activated V{alpha}24 NKT Cells.
Human V{alpha}24 NKT cells purified from umbilical cord blood were cultured with {alpha}-GalCer and IL-2 for 14 days (7) , and their cytotoxic activity against tumor cells was assessed. As shown in Fig. 1ACitation , >87% of the cultured cells were found to express the invariant V{alpha}24/V{beta}11 NKT cell antigen receptor. These cells displayed a potent cytotoxic activity against Daudi lymphoma (Fig. 1B, left)Citation , which was inhibited by concanamycin A, suggesting a perforin-dependent killing mechanism (Fig. 1B, right)Citation .



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  		Fig. 1. Antitumor cytotoxic activity of {alpha}-GalCer-activated human V{alpha}24 NKT cells. Freshly isolated V{alpha}24 NKT cells from cord blood were cultured for 14 days with CD3- cells as APCs in the presence of {alpha}-GalCer (10 ng/ml) and IL-2 (100 units/ml). A, representative flow cytometric profiles and frequency of V{alpha}24 NKT cells (boxed) before (left) and after the culture (right). B, perforin-mediated antitumor cytotoxicity of the activated V{alpha}24 NKT cells. The cytotoxicity was measured by 51Cr release assay on Daudi lymphoma cells (1 x 104; left panel). The activated V{alpha}24 NKT cells were pretreated with concanamycin A (•) or control DMSO ({circ}) for 2 h at 5% CO2, 37°C, and then used for cytotoxic assays (E/T ratio, 6; right panel).

 
Moreover, we demonstrated that a variety of human tumor cell lines were susceptible to the activated V{alpha}24 NKT cells. As shown in Fig. 2ACitation , K562, Daudi, and Molt-4 (hematopoietic tumors) were highly susceptible to the activated V{alpha}24 NKT cells. Similar susceptibility was shown by SK-Mel-28 and HMV-1 (malignant melanoma cell lines); PC10, PC6, PC13, and ABC-1 (lung cancer cell lines); RCM-1 (colon cancer line); TN-1 (neuroblastoma cell line); and HeLa cell lines were also considerably susceptible. On the other hand, certain cell lines, such as PANC-1 (pancreas cancer), Alexander hepatoma, and SHIN-3 (ovarian cancer), appeared to be relatively resistant. Con A blasts of normal PBLs were not susceptible by the activated V{alpha}24 NKT cells (Fig. 2A, bottom, right)Citation . We found no correlation between the levels of surface expression of class I MHC molecules on the tumor cells (Fig. 2B)Citation and the levels of cytotoxicity (Fig. 2A)Citation . Thus, the effector mechanisms of the activated V{alpha}24 NKT cells cannot be explained simply as a conventional NK cell killing.



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  		Fig. 2. Class I MHC-independent cytotoxic activity of the {alpha}-GalCer-activated V{alpha}24 NKT cells. A, cytotoxic activity of {alpha}-GalCer-activated V{alpha}24 NKT cells was examined on various human tumor cell lines ({circ}) and syngeneic ({square}) or allogeneic ({triangleup}) Con A-activated normal PBLs. B, expression of MHC class I molecules on target cells (shaded area) was determined by staining with anti-MHC class I monoclonal antibody (G46-2.6).

 
To further investigate the in vivo function of {alpha}-GalCer-activated V{alpha}24 NKT cells, we carried out a Winn’s assay (8). As shown in Fig. 3Citation , the tumor growth was dramatically inhibited if T.Tn tumor cells were inoculated together with activated V{alpha}24 NKT cells, suggesting cytotoxic activity of {alpha}-GalCer-activated V{alpha}24 NKT cells in vivo.



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  		Fig. 3. Inhibition of tumor growth in vivo by {alpha}-GalCer-activated V{alpha}24 NKT cells. A, human esophageal cancer T.Tn cells (1 x 107) were s.c. inoculated into the back of BALB/c nude mice with (•) or without ({circ}) activated V{alpha}24 NKT cells (1 x 107). Bars, SD. B, photographic view of tumors. Two representative mice with or without V{alpha}24 NKT cells are shown. Three independent experiments with a total of five mice in each group showed similar results.

 
Activation of V{alpha}24 NKT Cells Obtained from Patients with Malignant Melanoma.
In view of several reports suggesting an impairment of the cytotoxic activity of T or NK cells in tumor-bearing patients (12, 13, 14) , we investigated whether the V{alpha}24 NKT cells from tumor patients could be activated to exhibit cytotoxic activity. Our results demonstrated that the number of V{alpha}24 NKT cells in PBLs from 13 patients with malignant melanomas was significantly low compared with those found in umbilical cord bloods or in PBLs from adult individuals (Fig. 4A)Citation . However, the V{alpha}24 NKT cells in patients responded well to {alpha}-GalCer, and their numbers increased greatly during the 14-day culture (Fig. 4B)Citation . This increase in their cell number varied between 119 and 1449 times, which is as good as the expansion in healthy individuals (data not shown). In addition, the activated V{alpha}24 NKT cells from the patients were revealed to have cytotoxicity against various tumor cells, such as Daudi lymphoma and SK-Mel-28 melanoma cells (Fig. 4C)Citation . Therefore, V{alpha}24 NKT cells in tumor patients appeared to be functionally normal in terms of ligand-induced activation, expansion, and antitumor cytolytic activity.



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  		Fig. 4. V{alpha}24 NKT cells from patients with melanomas. A, numbers of V{alpha}24 NKT cells in umbilical cord blood (n = 21), PBLs of adults (n = 15), and PBLs of melanoma patients (n = 13) were calculated by flow cytometric analysis. The results are depicted as mean values; bars, SD. Statistical analysis was performed with the Mann-Whitney U test. *, P < 0.0001; **, P < 0.01. B, expansion of V{alpha}24 NKT cells upon stimulation with {alpha}-GalCer. PBLs from melanoma patients (n = 3) were cultured by the methods as described in Fig. 1Citation . The absolute numbers of V{alpha}24/V{beta}11 NKT cells were calculated by using flow cytometric analysis. Each symbol represents a single individual patient. C, cytotoxic activity of the activated V{alpha}24 NKT cells was assessed by 51Cr release cytotoxic assay on Daudi lymphoma and SK-Mel-28 melanoma cells. Bars, SD.

 
Efficient Antigen Presentation by DCs from Melanoma Patients.
Finally, we addressed the question whether DCs from melanoma patients preserved their capacity to present {alpha}-GalCer to stimulate NKT cells, because it is important to evaluate patient’s DC function for practical reasons before immunotherapy. For this purpose and based on the well-known capacity of human DCs to stimulate murine V{alpha}14 NKT cells (5) , murine V{alpha}14 NKT cells as an indicator were stimulated by {alpha}-GalCer-pulsed DCs obtained from a patient. As shown in Table 1Citation , stimulation indexes obtained by patient DCs were in the range of 14–74, which were similar to those observed by healthy volunteers. Therefore, {alpha}-GalCer-pulsed DCs obtained from malignant melanoma patients as well as those from healthy donors activated murine V{alpha}14 NKT cells equally well to induce significant proliferative responses.


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  		Table 1 Ability of patient’s DCs to present {alpha}-GalCera

 

   Discussion
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
REFERENCES
 
Here, we demonstrate that freshly isolated V{alpha}24 NKT cells from PBLs of tumor-bearing patients or healthy donors displayed perforin-dependent antitumor cytotoxicity in vitro (Figs. 1Citation , 2Citation , and 4Citation ) and in vivo (Fig. 3)Citation , after activation with {alpha}-GalCer. This cytotoxic activity was not dependent on the expression level of MHC class I molecules on the target cells, suggesting the effector mechanisms of V{alpha}24 NKT cells are different from those observed in conventional NK cells.

The {alpha}-GalCer/CD1d-NKT system reveals to be a promising new approach for immunotherapy aimed at treatment of human cancers for the following reasons: (a) the level of cytotoxicity of activated V{alpha}24 NKT cells is very high and effective against a wide variety of tumor cells (Fig. 2)Citation ; (b) normal cells are not susceptible to the activated V{alpha}24 NKT cells; (c) the activation of V{alpha}24 NKT cells by {alpha}-GalCer is totally dependent on a CD1d molecule, which is monomorphic among individuals (15) , indicating that {alpha}-GalCer can be applied to all patients, irrelevant to MHC haplotypes; (d) V{alpha}24 NKT cells are functionally normal, even in the tumor-bearing status, although the initial numbers of V{alpha}24 NKT cells in these patients were significantly lower than those found in healthy volunteers; (e) the antigen-presenting functions of DCs in cancer patients can be evaluated before immunotherapy by the assay system using mouse V{alpha}14 NKT cells as an indicator.

Extensive efforts have been made for the detection and isolation of the peptides bound to classical MHC molecules, which can be used as tumor vaccine (16 , 17) . In fact, some tumor antigens have been introduced to clinical trials with significant effects (16 , 17) . However, there are several theoretical and practical problems. Among others, one of the most critical is that the expression of MHC class I molecules on tumor cells in the tumor nests is quite variable (18 , 19) . Indeed, MHC low-expressing tumor cells are found to escape from the immunotherapy (20) . Another important problem is that MHC molecules are polymorphic; therefore, a peptide isolated from one patient with a certain MHC haplotype is likely to be irrelevant for other cancer patients with different MHC haplotypes. From an immunotherapy view point, the V{alpha}24 NKT cell system appears to have distinct advantages over other antitumor mechanisms. For example, CD1d is monomorphic among species, and human NKT cells kill the tumor cells expressing low levels of MHC in an NK-like mechanism. Therefore, some important problems raised in the CTL/MHC peptide therapy appear to be resolved. Thus, the combination of NKT cell and CTL/MHC peptide therapy appears to be a feasible and an approach worth developing, an approach that may become and efficient tool for the eradication of human cancers.

In addition, it is particularly interesting to note that the murine V{alpha}14 NKT cells can be used as an indicator to evaluate functions of patient DCs. It is important to know the functional ability of immune system in patients before immunotherapy, because patient immune functions, including antigen-presenting activity and/or lymphocyte functions, can be impaired (12, 13, 14) . Despite the above assumptions, the data shown in Table 1Citation have demonstrated clearly that human DCs from melanoma patients as well as healthy volunteers activate murine V{alpha}14 NKT cells with {alpha}-GalCer effectively. Because stimulation indexes obtained by DCs of patients are in a similar range to those of healthy individuals, we speculate that most melanoma patients with different clinical stages have normal DC functions. In addition, proliferative responses and cytolytic functions of V{alpha}24 NKT cells in patient PBLs are also normal (Fig. 4)Citation . Thus, by the experimental systems demonstrated in this report, we are able to evaluate the levels of immune functions in melanoma patients before immunotherapy, particularly whether patients can respond to {alpha}-GalCer.


   ACKNOWLEDGMENTS
 
We are grateful to Dr. Fidel Zavala for helpful comments and constructive criticism in the preparation of the manuscript. We also thank Kirin Brewery Co. Ltd. for providing glycolipid reagents and Hiroko Tanabe for secretarial work.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 This work is supported in part by Grant-in-Aid for Scientific Research on Priority Areas 06282103 from the Ministry of Education, Science, Sports and Culture. Back

2 To whom requests for reprints should be addressed, at Department of Molecular Immunology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan. Back

3 The abbreviations used are: {alpha}-GalCer, {alpha}-galactosylceramide; NK, natural killer; PBL, peripheral blood lymphocyte; DC, dendritic cell; APC, antigen-presenting cell; IL, interleukin; Con A, concanavalin A. Back

Received 6/15/99. Accepted 9/ 8/99.


   REFERENCES
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
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