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Clinical Cancer Research Vol. 11, 7322-7327, October 15, 2005
© 2005 American Association for Cancer Research

Imaging, Diagnosis, Prognosis

Increased Intratumor V{alpha}24-Positive Natural Killer T Cells: A Prognostic Factor for Primary Colorectal Carcinomas

Tsuyoshi Tachibana1, Hisashi Onodera1, Tatsuaki Tsuruyama2, Akira Mori1, Satoshi Nagayama1, Hiroshi Hiai3 and Masayuki Imamura1

Authors' Affiliations: Departments of 1 Surgery and Surgical Basic Science, and 2 Pathology and Biology of Diseases, Graduate School of Medicine, Kyoto University, Kyoto, and 3 Shiga Medical Center for Adults, Shiga, Japan

Requests for reprints: Hisashi Onodera, Department of Surgery and Surgical Basic Science, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawara-cho, Sakyo-ku, Kyoto 606-8507, Japan. Phone: 81-75-751-3627; Fax: 81-75-751-3219; E-mail: onohisa{at}kuhp.kyoto-u.ac.jp.


   Abstract
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 Abstract
Patients and Methods
 Results
 Discussion
 References
 
Purpose: Human invariant natural killer T (NKT) cells are novel, distinct lymphocyte populations with a restricted T-cell receptor repertoire (V{alpha}24-Vß11). They play a pivotal role in immunoregulation and in antitumor activities. This study focused on V{alpha}24+ NKT cells in colorectal carcinomas and their clinicopathologic significance.

Experimental Design: V{alpha}24+ NKT-cell infiltration immunohistochemistry was studied in a total of 103 colorectal carcinoma cases. The degree of NKT-cell infiltration in tumors was evaluated as low (<7 NKT cells/5 HPF) or high (≥7 NKT cells/5 HPF). The correlation between the degree of infiltrated V{alpha}24+ NKT cells and clinicopathologic variables was studied statistically.

Results: A small number of V{alpha}24+ NKT cells were found in the normal colorectal mucosa (2.6 ± 3.7 cells/5 HPF); however, their number increased remarkably in colorectal carcinomas (15.2 ± 16.3 cells/5 HPF; P = 0.0003) and a majority showed phenotype of activation. Higher NKT-cell infiltration was more frequent in women than in men (P = 0.034) and correlated with fewer lymph node metastases (P = 0.042). Patients with high NKT-cell infiltration showed higher overall (P = 0.018) as well as disease-free (P = 0.0006) survival rates. Intratumor NKT-cell infiltration was an independent prognostic factor for the overall (P = 0.033) and disease-free (P = 0.0064) survival rates.

Conclusions: Increased infiltration of V{alpha}24+ NKT cells was observed in colorectal carcinomas. Higher V{alpha}24+ NKT-cell infiltration in colorectal carcinomas was an independent prognostic factor for favorable prognosis.

Natural killer T (NKT) cells have been recently recognized as a novel subset of lymphoid cells (1). NKT cells, which share the characteristics of both T and natural killer cells, constitute a unique class of the T lymphocyte lineage. They have an extremely restricted T-cell receptor (TCR) repertoire consisting of an invariant V{alpha}24-J{alpha}18 chain (formerly V{alpha}24-J{alpha}Q) paired with a Vß11 chain in human peripheral blood (2, 3). These cells recognize glycolipid antigens, such as {alpha}-galactosylceramide presented by MHC class I–like molecules CD1d on antigen-presenting cells (4–8). It has been assumed that NKT cells play a role in immunoregulation. When activated, NKT cells immediately produce a large amount of proinflammatory T helper 1 cytokines (e.g., IFN-{gamma} and tumor necrosis factor-{alpha}) and antiinflammatory T helper 2 cytokines [e.g., interleukin (IL)-4, IL-10, and IL-13; refs. 4, 7, 9–12]. NKT cells have been implicated in the control of infection (13–15), inflammatory bowel diseases (16, 17), and abortion (18), as well as in transplantation tolerance (19, 20), the suppression of autoimmune diseases (21–24), and the regulation of allergic disorders (25, 26). Moreover, NKT cells have been postulated to play protective as well as tolerogenic roles in tumor immunity (12, 27–34).

NKT cells are mainly localized in the thymus, bone marrow, liver, and spleen, but they are rare in the lymph nodes (4, 34). In the gastrointestinal tract, Bannai et al. (35) found a considerable number of NKT cells intraepithelially in the colon of mice. More recently, O'Keeffe et al. (36) reported that CD161+ T cells are the major natural killer receptor–positive cell population in the intestine and that the natural killer receptor–positive T cells are not much more frequent in colorectal carcinomas than in adjacent tumor-free tissue. However, few reports have been available on human NKT cells in normal and neoplastic colon.

In the present study, to evaluate the prognostic potential of intratumor NKT-cell infiltration in colorectal carcinomas, we investigated intratumor TCR-V{alpha}24-positive cells in 103 primary colorectal carcinoma samples.


   Patients and Methods
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 Patients and Methods
Results
 Discussion
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Study population. The clinical records of patients who had been diagnosed with primary colorectal carcinoma and had undergone resection with curative intent at the Department of Surgery and Surgical Basic Science, Kyoto University, between 1996 and 1997, were carefully examined. After excluding those who had died within 30 days of the surgery and those who had died from causes unrelated to colorectal carcinoma, a total of 103 patients (65 males and 38 females) underwent full survival analysis over a median follow-up time of 1,914 days. The mean age of the patients at diagnosis was 64.9 ± 12.2 years. In the tumor-node-metastasis (TNM) classification system (37), 37% were pTNM stage I, 21% were stage II, 29% were stage III, and 13% were stage IV. None had received preoperative chemotherapy or radiotherapy. Patients with stage III or IV colorectal carcinomas were given postoperative chemotherapy consisting of 5-fluorouracil. Written informed consent was obtained from all the patients.

Immunohistochemistry. Immunohistochemistry was carried out using the catalyzed signal amplification system (DAKO, Carpinteria, CA) according to the manufacturer's instructions with minor modifications. In brief, 4-µm sections of formalin-fixed and paraffin-embedded tissues were deparaffinized and rehydrated, and an antigen retrieval procedure was done using Target-Retrieval Solution (DAKO). Sections were incubated overnight at 4°C with a 1:100 diluted primary antibody. For primary reagents, we used monoclonal antibodies C15 (TCR-V{alpha}24, Immunotech SA, Marseilles, France), C21 (TCR-Vß11, Immunotech), MC-1 (CD56, DAKO), NK1 (CD57, DAKO), DX12 (CD161, BD Biosciences, San Diego, CA), CH11 (CD69, Lab Vision, Fremont, CA), MD-1 (IFN-{gamma}, Biosource, Camarillo, CA), anti-granzyme B (WAKO, Osaka, Japan), and the polyclonal antibody to FasL (Histofine, Nichirei, Tokyo, Japan). The endogenous peroxide was quenched by incubation with 3.0% hydrogen peroxide/methanol after the sections had been incubated with the second antibody. Horseradish peroxidase–conjugated extravidin (Sigma, St. Louis, MO) was used instead of streptavidin. Nuclei were counterstained with Mayer's hematoxylin (WAKO). For immunofluorescence staining, phycoerythrin-conjugated streptavidin and fluorescein-streptavidin (Vector Laboratories, Burlingame, CA) were used in place of streptavidin. Twenty-four sections of adjacent normal colorectal mucosa were also examined. The negative control consisted of sections that were treated with the same protocol but without the primary antibody. Specimens were examined under Olympus BX50 and Olympus AX80TR microscopes (Olympus, Tokyo, Japan).

Histologic evaluation of tumor and natural killer T cells. Histologic grading of the colorectal carcinomas was done according to the criteria of the WHO (38). Lymphatic invasion and venous invasion were evaluated following the rules proposed by the Japanese Research Society for Cancer of the Colon and Rectum (39).

Human V{alpha}24+ NKT cells express invariant T-cell receptor composed of V{alpha}24-J{alpha}18 (5, 6). It could be assumed that the majority of V{alpha}24-positive cells represent invariant V{alpha}24+ NKT cells. V{alpha}24+ NKT cells were counted in five randomly selected x200 fields of the tumor mass and in adjacent non–tumor mucosa or submucosa by two investigators who were blinded to the clinical data. NKT cells infiltrating in the tumor were defined as V{alpha}24+ cells found simultaneously with tumor tissues in the same field to avoid counting the incidental bystanders as much as possible. The degree of V{alpha}24+ NKT-cell infiltration was scored as either low if less than seven V{alpha}24+ NKT cells were found in five intratumor fields, or high if seven or more V{alpha}24+ NKT cells were found. This number was selected to give the highest significance in the statistical analysis of prognosis.

Statistical analysis. Statistical analyses were done with StatView-J 5.0 software (SAS Institute, Cary, NC). The relationship between clinicopathologic factors and NKT-cell infiltration was evaluated by the {chi}2 test. The unpaired Mann-Whitney U test was used to compare the number of NKT cells in normal mucosa and in colorectal tumors. The Kaplan-Meier method was used to obtain survival curves. The log-rank test was used to compare survival based on NKT-cell infiltration. Multivariate analysis was done by the Cox proportional hazard regression model. P < 0.05 was considered statistically significant.


   Results
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 Abstract
 Patients and Methods
 Results
Discussion
 References
 
Increased V{alpha}24+ natural killer T cells in colorectal carcinomas. Combined immunostaining with fluorescence-labeled antibodies revealed that an increased number of NKT cells bearing a T-cell receptor repertoire of V{alpha}24 and Vß11 infiltrated colorectal carcinomas (Fig. 1A). V{alpha}24+ NKT cells expressed combinations of Vß11, CD56, CD57, or CD161 (Fig. 1B, C, D, and E). In normal colorectal tissues, a few V{alpha}24+ NKT cells were found mainly in the interstitial region of the submucosa (data not shown) and sometimes in the colonic lymphoid follicle and/or intraepithelial region (data not shown). V{alpha}24+ NKT cells were large lymphoid cells with multilobulated nuclei (Fig. 1F, inset).



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  		Fig. 1. V{alpha}24 NKT cells express TCR-Vß11 and diverse natural killer cell markers. A, immunofluorescent staining of colorectal carcinomas with anti-TCR-V{alpha}24 (green) and anti-TCR-Vß11 (red). Double-positive cells were stained greenish-yellow. Original magnification, x200. B, immunofluorescent staining of colorectal carcinomas with anti-TCR-V{alpha}24 (green) and anti-TCR-Vß11 (red). Original magnification, x400. C, immunofluorescent staining of colorectal carcinomas with anti-TCR-V{alpha}24 and anti-CD56 (red). Original magnification, x400. D, immunofluorescent staining of colorectal carcinomas with anti-TCR-V{alpha}24 (green) and anti-CD57 (red). Original magnification, x400. E, immunofluorescent staining of colorectal carcinomas with anti-TCR-V{alpha}24 (green) and anti-CD161 (red). Original magnification, x400. F, representative case of NKT-cell infiltration in colorectal carcinomas. A positive signal is seen as brown staining. All sections were counterstained with hematoxylin. Original magnification, x200. Inset, a V{alpha}24 NKT cell, i.e., a large lymphocyte with multilobulated nuclei (x1,000).

 
The number of V{alpha}24+ NKT cells in colorectal carcinomas (15.2 ± 16.3 cells/5 HPF; n = 103) was significantly higher than that in normal mucosa (2.6 ± 3.7, n = 24; P = 0.0003). V{alpha}24+ NKT cells were found also in the tumor-infiltrating vessels (data not shown).

Activation of V{alpha}24+ natural killer T cells in colorectal carcinomas. V{alpha}24+ NKT cells infiltrating colorectal carcinomas seemed activated because they were positively stained for the early activation markers, CD69 and FasL (Fig. 2A and B). They also expressed active effector molecules IFN-{gamma} and granzyme B (Fig. 2C and D). The fraction of CD69-positive NKT cells in colorectal carcinomas was 81.9%, whereas in the normal mucosa, it was 12.5% (P < 0.001). The fraction of FasL-positive cells was 76.6% in the former and 21.4% in the latter (P < 0.001).



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  		Fig. 2. Expression of activation marker CD69 and effector molecules by activated NKT cells in colorectal carcinomas. Double immunostaining with anti-TCR-V{alpha}24 (green) and CD69 (A), FasL (B), granzyme B (C), and IFN-{gamma} (D; red). Double-positive cells are seen as greenish-yellow. Original magnification, x400.

 
V{alpha}24+ natural killer T-cell infiltration and colorectal carcinoma clinicopathologic factors. Among colorectal carcinoma patients, the degree of V{alpha}24+ NKT-cell infiltration varied from case to case. Figure 1F shows representative colorectal carcinomas with high NKT-cell infiltration. The colorectal carcinoma patients were subdivided into two groups, designated high (65 patients) and low (38 patients), according to the degree of NKT-cell infiltration. We compared the clinicopathologic variables in these two groups (Table 1). There was no significant correlation between NKT-cell infiltration and age, tumor location, histologic differentiation, lymphatic invasion, venous invasion, tumor depth, distant metastasis, or TNM stage (Table 1). However, the patients with high NKT-cell infiltration had a significantly lower incidence of regional lymph node metastasis (21 of 65) than those with low NKT-cell infiltration (20 of 38; P = 0.042). Furthermore, many more female than male patients showed high NKT-cell infiltration (P = 0.037; Table 1).


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  		Table 1. Clinicopathologic variables and NKT-cell infiltration

 
V{alpha}24+ natural killer T-cell infiltration as a colorectal carcinoma prognostic factor. As seen in Fig. 3A, overall survival was found to be significantly higher in patients with high NKT-cell infiltration (n = 65) than in those with low NKT-cell infiltration (n = 38; P = 0.018). The univariate analysis revealed that lymph node metastasis (P = 0.0011), NKT-cell infiltration (P = 0.024), and distant metastasis (P < 0.0001) were primary factors influencing favorable overall survival. Multivariate analysis showed that NKT-cell infiltration (P = 0.033) and distant metastasis (P < 0.0001) were independent prognostic factors for survival (Table 2).



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  		Fig. 3. Intratumor NKT cells as a prognostic factor in colorectal carcinoma patients. Kaplan-Meier analysis for overall survival and degree of NKT-cell infiltration in colorectal carcinomas (log-rank test, P = 0.0006). Kaplan-Meier analysis for disease-free survival (log-rank test, P = 0.018).

 

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  		Table 2. Univariate and multivariate analysis of prognostic factors for overall survival (n = 103)

 
Subsequently, we compared the disease-free survival rate in the two groups after exclusion of the 13 patients with stage IV disease. As shown in Fig. 3B, the patients with high NKT-cell infiltration (n = 58) had a significantly longer disease-free survival rate than those with low NKT-cell infiltration (n = 32; P = 0.0006). The univariate analysis revealed that venous invasion (P = 0.036), lymph node metastasis (P = 0.0081), and NKT-cell infiltration (P = 0.0031) were significant prognostic factors. Multivariate analysis showed that only the grade of NKT-cell infiltration (P = 0.0064) was an independent prognostic factor for disease-free survival (Table 3).


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  		Table 3. Univariate and multivariate analysis of prognostic factors for disease-free survival (n = 90)

 

   Discussion
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 Patients and Methods
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 Discussion
References
 
The role of NKT cells in tumor immunity has not been studied extensively. NKT cells are currently classified into three types (40): type I, classical NKT cells; type II, non-classical NKT cells; and NKT-like cells or CD1d-independent NK1.1+ T cells. Classical NKT cells expressed TCR-Vß11 and/or CD161 (6, 40). Human classical NKT cells used an invariant TCR-V{alpha}24, whereas mouse NKT cells used TCR-V{alpha}14 (1, 28). In contrast, the T-cell receptor V regions used by type II and NKT-like cells are highly diverse. The observation that intratumor V{alpha}24+ T cells invariably coexpressed TCR-Vß11 and other natural killer markers indicates that they are invariant V{alpha}24+ NKT cells.

In this study, we found that the density of V{alpha}24+ NKT cells in colorectal carcinomas increased significantly. Thus far, other groups have reported a remarkable decrease of invariant NKT cells in peripheral blood in patients with advanced cancers (41, 42). We observed that V{alpha}24+ NKT cells actually existed in the luminal space of tumor-infiltrating vessels. These observations suggest that V{alpha}24+ NKT cells could migrate from the peripheral blood to the tumors.

The present study indicates that the accumulation of intratumor NKT cells provide a better prognosis for colorectal carcinoma patients. However, the effector mechanism of antitumor activity has remained speculative. We found that the higher fraction of V{alpha}24+ NKT cells in colorectal carcinomas expressed activation marker CD69 than those in normal mucosa, and probably execute local cytotoxicity against tumor cells by IFN-{gamma} and apoptosis-inducing molecules including FasL, perforin, and granzyme B (29). In this way, NKT cells may play a role in the primary defense against colorectal carcinomas by induction of tumor cell death. Alternatively, the increase of NKT cells in the tumors may represent a surrogate marker of antitumor activities.

Coca et al. (43) have previously reported that colorectal carcinomas with higher CD57+ natural killer cell infiltration have better prognosis. Because the CD57+ cell population includes NKT cells, the present observation is partly compatible with their conclusion.

Another interesting feature is that V{alpha}24+ NKT cells play a role in the inhibition of lymph node metastasis of colorectal carcinomas. Although V{alpha}24+ NKT cells are normally rare in lymph nodes (4, 34), a large number of these cells appear in the metastasis-free swollen lymph nodes of colorectal carcinoma patients. The precise mechanism for V{alpha}24+ NKT cells to inhibit lymph node metastasis has remained obscure. However, it is possible that activated V{alpha}24+ NKT cells migrate to regional lymph nodes, where they injure the metastasizing colorectal carcinoma cells and consequently prevent lymph node metastasis.

Statistically, patients with higher intratumor NKT-cell infiltration showed significantly longer overall and disease-free survival rates. This is consistent with the fact that these patients had much less lymph node metastasis. Our findings support intratumor infiltration of NKT cells as a promising variable to predict the prognosis of patients with colorectal carcinoma.


   Footnotes
 
Grant support: Grant-in-Aid for Scientific Research (#15591400) from the Ministry of Education, Science, Sports, and Culture of Japan.

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.

Note: For pathology findings, contact Dr. Tatsuaki Tsuruyama, tsuruyam{at}path1.med.kyoto-u.ac.jp.

Presented in part at the 20th Biennial Congress of the International Society of University Colon and Rectal Surgeons, Budapest, Hungary, June 7, 2004.

Received 4/21/05; revised 7/19/05; accepted 7/25/05.


   References
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 Patients and Methods
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 Discussion
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