|Year : 2017 | Volume
| Issue : 6 | Page : 194-199
The producing capabilities of Interferon-γ and Interleukin-10 of spleen cells in primary and metastasized oral squamous cell carcinoma cells-implanted mice
Yasuka Azuma1, Masako Mizuno-Kamiya2, Eiji Takayama3, Harumi Kawaki3, Toshihiro Inagaki4, Eiichi Chihara5, Yasunori Muramatsu6, Nobuo Kondoh3
1 Department of Oral Biochemistry, Division of Oral Structure, Function and Development, Asahi University School of Dentistry, Gifu; Department of Anesthesiology, Division of General Medicine, Chemistry Laboratory, Gifu, Japan
2 Department of Management and Information Studies, Asahi University School of Business Administration, Gifu, Japan
3 Department of Oral Biochemistry, Division of Oral Structure, Function and Development, Asahi University School of Dentistry, Gifu, Japan
4 Department of Oral and Maxillofacial Surgery, Division of Reparative and Regenerative Medicine, Institute of Medical Science, Mie University Graduate School of Medicine, Mie, Japan
5 Department of Anesthesiology, Division of General Medicine, Chemistry Laboratory, Asahi University School of Dentistry, Gifu, Japan
6 Department of Oral and Maxillofacial Surgery, Division of Oral Pathogenesis and Disease Control, Asahi University School of Dentistry, Gifu, Japan
|Date of Web Publication||29-Dec-2017|
Department of Management and Information Studies, Asahi University School of Business Administration, 1851 Hozumi, Mizuho, Gifu 501-0296
Source of Support: None, Conflict of Interest: None
Aim: The aim of this study is to compare the immunomodulatory effects exerted by primary versus metastasized oral squamous cell carcinoma (OSCC) cells.
Methods: Mouse OSCC cell line Sq-1979, 233 cells established from implanted Sq-1979 cells, and L cells established from the metastasized lymph node tissues of Sq-1979-implanted mice were subcutaneously inoculated into the later abdominal area of syngeneic C3H mice. The producing capabilities of interferon (IFN)-γ, a Th1 cytokine, and interleukin (IL)-10, a Th2 cytokine, by anti-CD3 antibody-stimulated spleen cells were investigated in tumor bearing-mice.
Results: The quantity of IFN-γ produced by stimulated spleen cells was significantly suppressed in the mice implanted with Sq-1979, 233, and L cells. Conversely, the production of IL-10 was significantly elevated in Sq-1979 and 233 cell-implanted mice while markedly suppressed in L cell-implanted mice.
Conclusion: Our results suggest that the metastasized L cells have acquired differential immunomodulatory functions compared to the original Sq-1979 and primary 233 cells.
Keywords: Interferon-γ, interleukin-10, metastasized, oral squamous cell carcinoma, spleen cells
|How to cite this article:|
Azuma Y, Mizuno-Kamiya M, Takayama E, Kawaki H, Inagaki T, Chihara E, Muramatsu Y, Kondoh N. The producing capabilities of Interferon-γ and Interleukin-10 of spleen cells in primary and metastasized oral squamous cell carcinoma cells-implanted mice. Cancer Transl Med 2017;3:194-9
|How to cite this URL:|
Azuma Y, Mizuno-Kamiya M, Takayama E, Kawaki H, Inagaki T, Chihara E, Muramatsu Y, Kondoh N. The producing capabilities of Interferon-γ and Interleukin-10 of spleen cells in primary and metastasized oral squamous cell carcinoma cells-implanted mice. Cancer Transl Med [serial online] 2017 [cited 2019 Oct 23];3:194-9. Available from: http://www.cancertm.com/text.asp?2017/3/6/194/221913
| Introduction|| |
Malignancy of tumors is not only promoted by aggressive phenotypes of tumor cells per se but is also regulated by the immunological response influencing the microenvironments of tumor tissues. The high density of lymphocyte infiltration has been identified as a marker in head and neck squamous cell carcinoma. Productions of several cytokines including interferon (IFN)-γ, IL-10, IL-18, and IL-12 are closely correlated with the prognosis of hepatocellular carcinoma (HCC) patients., IL-10 expression is also a prognostic factor for thyroid cancer, OSCC, and gastrointestinal malignancies., Enhanced expressions of IL-18 can play an important role in progression and metastasis of gastric cancer and prostate cancer.,,,,
Depending on the cytokine profile, the immune responses have been classified into at least 2 helper T cell subsets that function distinctly. The cytokines produced by the Th1 and Th2 cell subsets are important for the effective function and immune response of T lymphocytes in regulating the distinct differentiation of these cells. It has been reported that an imbalance between Th1 and Th2 immune response has a correlation with immune dysregulation in various malignancies. The Th1 and Th2 balance has been evaluated in bladder carcinoma, colorectal cancer, breast cancer, and melanoma patients.,,, In line with these observations, the IFN-γ-producing capability of LPS-stimulated peripheral blood (PB) is significantly reduced in HCC patients. These studies comparing the Th1/Th2 balance of cancer patients demonstrated that they had a Th1 deficit whereas Th2 cytokine was found to have increased.
We have previously established a cancer model of oral malignancy by implanting a mouse oral squamous cell carcinoma (OSCC) cell line, Sq-1979, and subclones including metastasized cells from lymph node tissues of Sq-1979-implanted mice. In this study, we compared the Th1/Th2 cytokine producing capability of spleen cells derived from primary and subclonal Sq-1979-implanted mice; in addition, we evaluated the diagnostic significance for oral malignancy in the mice implanted with subclonal cells.
| Methods|| |
Five-week-old male C3H/HeN mice were purchased from Chubu Kagaku Shizai Co., Ltd. (Nagoya, Japan) and maintained ad libitum on Oriental MF solid chow (Oriental Yeast Co., Tokyo, Japan) for one week before the start of experiments. This study was approved by the Animal Ethics Committee of Asahi University (No. 12-001).
Cells and establishment of subclones
The C3H mouse OSCC cell line, Sq-1979, was obtained from the RIKEN BioResource Center (Ibaraki, Japan). Cells were grown in Eagle's minimum essential medium (E-MEM; Wako, Osaka, Japan), supplemented with 10% fetal bovine serum (FBS, Biowest, Nuaillé, France), and 1% Pen Strep (penicillin 10,000 U/mL, streptomycin 10,000 μg/mL; Gibco®, Life Technologies, Grand Island, NY, USA). Establishments of Sq-1979 subclones are as described. Briefly, a 6-week-old male C3H/HeN mice were subcutaneously inoculated in the posterior neck area with ten million of Sq-1979 cells suspended in 0.1 mL of saline. After 3 months, metastasized regional lymph nodes were dissected to isolate attached cells. Then, metastasized subclones, including L2–3, L3–5, L5–11, L6–8, and L6–9 cells, were isolated with a serial-limiting dilution method. Using the same procedure, 233-1 and 233-11 cells were isolated from the primary OSCC tissues at 2 months after implantation. For establishments of 233 cells, ten million of Sq-1979 cells were implanted subcutaneously into the lateroabdominal area of mice.
The OSCC cell lines were harvested, washed twice with saline, and resuspended at 1 × 108 cells/mL (Sq-1979-and 233-series-subclones) or 1 × 107 cells/mL (L-series-subclones). Cell suspension of 0.1 mL was injected subcutaneously into the lateroabdominal area of the 6-week-old male C3H/HeN mice. Control mice were injected with only saline. Tumor size was measured every week with a caliper, and the tumor volumes were calculated as length × width 2 × 0.52. To analyze cytokine production, the mice were sacrificed 3 or 4 weeks after implantation.
Preparation of spleen cells from tumor-bearing mice
Three or four weeks after implantation of Sq-1979-and 233-series-subclones or L-series-subclones, respectively, spleens were removed from tumor-bearing mice. Then, the spleen cells were isolated by smashing the tissue with stainless steel mesh and resuspended in Roswell Park Memorial Institute (RPMI) 1640 medium (Sigma-Aldrich, St. Louis, MO, USA) containing 10% FBS (Biowest), 50 μM 2-mercaptoethanol (Nacalai tesque, Kyoto, Japan), and a 1% antibiotic-antimycotic solution (penicillin 10,000 U/mL, streptomycin 10,000 μg/mL, amphotericin B 25 μg/mL; Gibco®, Life Technologies). Cells were collected by centrifugation at 1,500 rpm for 5 min and then resuspended in a 2 mL red blood cell lysis buffer (10 mM Tris-HCl (pH 7.3) containing 140 mM NH4 Cl and 1 mM Na2 ethylenediaminetetraacetic acid [EDTA]). After incubation for 5 min at room temperature, the cells were washed three times with the same RPMI-1640 medium by centrifugation at 1,500 rpm for 5 min. The spleen cells were resuspended in the RPMI-1640 medium and filtered using a cell strainer (Falcon®, Corning, NY, USA) to remove the residue.
Analysis of cytokine production from spleen cells
The spleen cell suspension (4 × 106/mL) from tumor-bearing mice was plated (0.1 mL/well, in triplicate) in a flat-bottom 96-well tissue culture plate (3599, Corning), on which 1 μg/mL of anti-CD3 monoclonal antibody (mAb) (145-2C11, BD Biosciences) had been immobilized (100 μL/well) at 4°C overnight. The cells were incubated for 48 h in 5% CO2 at 37°C, and then, the supernatant was harvested by centrifugation at 3,000 rpm for 5 min and stored at − 80°C. Production of IFN-γ, IL-10 and IL-4 in the supernatant of the cell cultures was assayed by enzyme-linked immunosorbent assay (ELISA) using BD OptE1A Set (BD Biosciences).
The OSCC cells were injected subcutaneously into the later abdominal area of two 6-week-old male C3H/HeN mice and the tumors were harvested 30 days later. The tumor tissues were fixed with 4% paraformaldehyde and embedded in paraffin.
Immunohistochemistry for alfa-smooth muscle actin (α-SMA) was performed using a Histofine ® MOUSESTAIN KIT (Nichirei Biosciences Inc., Tokyo, Japan) which used the universal immuno-enzyme polymer method, the patented technology of Nichirei Biosciences. For antigen retrieval, the sections for α-SMA were treated with EDTA solution (pH 9.0) at 95°C for 20 min. After blocking the tissue sections with reagent A, they were incubated with antiα-SMA (Clone 1A4)-mAb (1:800) (Thermo Fisher Scientific Inc., Runcorn, Cheshire, UK) for 5 min at room temperature and then washed in phosphate-buffered saline solution. After blocking with reagent B, the tissue sections were stained with Simple Stain Mouse Max PO (M) and were visualized with DAB solution. To compare the morphologic appearances, paraffin sections were also stained with hematoxylin and eosin.
The data are expressed as means ± standard deviation. Pearson's correlation coefficient was applied to analyze the correlation between cytokine-producing capabilities and tumor sizes. The significance level (two-tailed probability) was tested using a correlation coefficient r table. For ELISA, Student's t-test was applied to determine the significance of differences between the two groups. P < 0.05 was considered to be statistically significant.
| Results|| |
Representative morphology of tumor tissues
Morphological appearances of tumor tissues from Sq-1979 cell and L5–11-implanted C3H mice are shown in [Figure 1]. Sq-1979 cells showed alveolar configuration among stromal cells [Figure 1]a. On the other hand, L5–11 cells showed diffusive, poorly marginated structures [Figure 1]b. α-SMA positive-cells, which have been traditionally defined as cancer-associated fibroblasts (CAFs), were detected among stromal cells of both tumor tissues [Figure 1]c and [Figure 1]d. The expression level of α-SMA was comparable in the two tumor tissues.
|Figure 1: (a and b) Morphological appearances of tumor tissues from Sq-1979-and L5–11-bearing C3H mice, 30 days after the OSCC implantation. H- and E-stained sections of tumor tissues (a: Sq-1979 and b: L5–11). (c and d) Anti-alfa-smooth muscle actin-stained sections of tumor tissues (c: Sq-1979 and d: L5–11). (e and f) Negative-stained sections of tumor tissues (e: Sq-1979 and f: L5–11) (×200). Arrows were placed to indicate tumor cell mass|
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Interferon-γ-producing capability of spleen cells in Sq-1979, 233-11, and L5–11-bearing mice
To examine the antitumor immunity of tumor-bearing mice, the concentrations of IFN-γ and IL-10 in serum were measured. However, neither IFN-γ nor IL-10 was detected in serum from all of mice used (data not shown). Then, the production of Th1 and Th2 cytokines from anti-CD3 stimulated spleen cells were compared among these animals. As shown in [Figure 2]a,[Figure 2]b,[Figure 2]c, the production of Th1 cytokine, IFN-g in spleen cells from all of the tumor-bearing mice was significantly reduced compared to that shown in control mice. The production was proportionally reduced depending on the tumor volumes, respectively. Among them, the rate of reduction seemed to be most prominent in the production of L5–11-bearing mice compared to that of Sq-1979-and 233-11-bearing mice. As shown in [Figure 2]d,[Figure 2]e,[Figure 2]f, the production of Th2 cytokine, IL-10, in spleen cells was also significantly reduced in L5–11-bearing mice while interestingly enhanced in Sq-1979-bearing mice. The IL-10 production in 233-11-bearing mice was not significantly changed compared to that in control mice. The production of another Th2 cytokine, IL-4, was also significantly reduced in L5–11-bearing mice; however, that was unchanged in 233-11-and Sq-1979-bearing mice, respectively [Figure 2]g,[Figure 2]h,[Figure 2]i.
|Figure 2: Relationship of tumor size to cytokine-productions from anti-CD3 monoclonal antibody-stimulated-spleen cells in Sq-1979, 233-11, and L5–11-bearing mice. (a, d, and g) Sq-1979-bearing mice (n = 4) and control mice (n = 5) were used. (b, e, and h) 233-11-bearing mice (n = 7) control mice (n = 5) were used. (c, f, and i) L5–11-bearing (n = 4) control mice (n = 2) were used. Data are expressed as a percentage of the control group which were injected with only saline. Each symbol represents an individual mouse. Values in triplicates were described as mean ± standard deviation r is the Pearson's correlation. *P < 0.05; **P < 0.01|
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Interferon-γ-and interleukin-10-producing capability of spleen cells in mice implanted with oral squamous cell carcinoma subclones
Since the production of IFN-γ and IL-10 seemed to be regulating the antitumor immune response, we then compared their producing capability among several subclones. As shown in [Figure 3], the production of IFN-γ was markedly reduced in spleen cells from all of the mice implanted with L (2–3, 3–5, 5–11 and 6–8), and 233 (-1 and -11), as well as Sq-1979 (-1, -2 and -3) cells, respectively. On the other hand, the production of IL-10 was significantly enhanced in the spleen cells of Sq-1979-implanted mice. Consistent, but not statistically significant, trend was also observed in the spleen cells of 233-1 and 233-11 cell-implanted mice. In contrast, IL-10 production was reduced in spleen cells of L3–5, L5–11, and L6–8 cell-implanted mice compared to control mice. These results suggested that the production of IL-10 was bifurcationally regulated in OSCC-bearing mice depending on the status of the metastases.
|Figure 3: Differential effects of oral squamous cell carcinoma subclones on interferon-g and interleukin-10-productions from spleen cells stimulated with anti-CD3 monoclonal antibody. Data are expressed as a percentage of the control group mice which were injected with only saline. Three to five control mice were used. Values were described as mean ± standard deviation (n > 3 except for Sq 1979-2, 3 and 233-1). Values were described as mean (n = 2, Sq-1979-2, 3 and 233-1). *P < 0.05; **P < 0.01|
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| Discussion|| |
Compared to parental Sq-1979 and 233 cells, most L cells represent a higher growth rate and implantability and also confer lower survival rates in the implanted mice. The expression of Fyb and Slc16a13 was also significantly elevated in L cells than in Sq-1979 and 233 cells. Hence, the majority of the L cells represent highly malignant phenotypes.
Our results demonstrated that the production of Th1 cytokine, IFN-γ in spleen cells from all the tumor-bearing mice was significantly reduced compared to that in control mice. The production of Th2 cytokine, IL-10, in spleen cells was also reduced in metastasized tumor mice implanted with metastasized tumor cells, while, interestingly, enhanced in mice implanted with primary tumor cells. Previously, we have reported that the IFN-γ-producing capability of PB was the highest in Stage I patients suffering from hepatitis C virus-related HCC and gradually decreased with the tumor progression. By contrast, the IL-10-, IL-18-and IL-12-producing capabilities of PB increased from Stage I to III. These findings are consistent with the results of this study.
IL-10, produced by Th2 cells, is a cytokine capable of suppressing T-cell proliferative responses and eliciting tolerance in T cells by selective inhibition of the CD28 costimulatory pathway, thereby inhibiting the production of cytokines including IFN-γ. IL-10 and tumor growth factor (TGF)-β1 play a particularly significant role for Tregs (The regulatory T cell)-mediated immunosuppression in the tumor microenvironment. IL-4, another cytokine closely linked to Th2 cells, is silenced by IFN-γ in the Th1 lineage. Therefore, we observed increased production of IL-10 in the stimulated spleen cells from Sq-1979 or 233 cell-implanted mice, which may lead to the reciprocal suppression of IFN-γ. However, in most L cell-implanted mice, the production of both IL-10 and IFN-γ in stimulated spleen cells was markedly reduced, suggesting differential immune-modulating effect by primary versus metastatic tumors.
We have already examined the distribution of myeloid-derived suppressor cells (MDSCs) in Sq-1979 and L cell-bearing mice  and revealed that the population of polymorphonuclear-myeloid-derived suppressor cell (PMN-MDSC) was significantly increased in OSCC tissues and spleen cells in L cell-bearing mice but not in the control or Sq-1979 cell-bearing mice. Therefore, our results suggest that the stronger immune suppression exerted in L cell-bearing mice over Sq-1979-bearing ones is potentially mediated by the PMN-MDSC. The possibility is also supported by the observation that the number of both CD4+ and CD8+ T cells among spleen cells significantly decreased in L cell-bearing mice. In addition, we demonstrated previously that Fyn mRNA is expressed at higher level in L5–11 cells compared to Sq1979 cells. Fyn is also known as adhesion and degranulation-promoting adaptor protein (ADAP). ADAP enhances the expression of programmed cell death receptor (PD)-1 in CD8+ T cells and reduces the cytotoxic T lymphocytes (CTL) cytotoxicity. Although the mechanism by which FYB protein from OSCC can affect T lymphocytes has yet to be investigated, we speculate that FYB may promote tumor progression by reducing antitumor immunity in L cells.
Our results strongly suggest that the regulatory mechanism of antitumor immunity is drastically changed among the mice implanted with primary versus metastasized OSCC cells. In the tumor microenvironment of OSCCs, CAF-educated CD14-positive cells repress T cell function via the activities of IL-10 and TGF-b. Therefore, CAF-educated CD14-positive cells may be a mediator in reducing the production of IFN-γ in the antigen-stimulated spleen cells from Sq-1979 cell-bearing mice. Fibroblast-activating protein positive CAFs abrogate anti-CTLA4 and anti-PD-L1, antagonists of immunological checkpoints. Our results demonstrate that there must be other immune-suppressive mechanism (s) than regulated by MDSCs, which could be mediated by humoral factor (s) among tumor microenvironment of OSCC tissues. Further study that aims to identify the immune-regulatory factor (s) of OSCC cells could better clarify the mechanisms of protumoral immunity associated with the OSCC progression.
The authors would like to express their deepest thanks to Ms. Masako Sawada for her excellent secretarial assistance.
Financial support and sponsorship
This work was financially supported in part by the Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science KAKENHI Grant Number (JP26463055).
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
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