Critical role for tumor necrosis factor-related apoptosis-inducing ligand in immune surveillance against tumor development - PubMed (original) (raw)

Kazuyoshi Takeda et al. J Exp Med. 2002.

Abstract

Natural killer (NK) cells and interferon (IFN)-gamma have been implicated in immune surveillance against tumor development. Here we show that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) plays a critical role in the NK cell-mediated and IFN-gamma-dependent tumor surveillance. Administration of neutralizing monoclonal antibody against TRAIL promoted tumor development in mice subcutaneously inoculated with a chemical carcinogen methylcholanthrene (MCA). This protective effect of TRAIL was at least partly mediated by NK cells and totally dependent on IFN-gamma. In the absence of TRAIL, NK cells, or IFN-gamma, TRAIL-sensitive sarcomas preferentially emerged in MCA-inoculated mice. Moreover, development of spontaneous tumors in p53(+/-) mice was also promoted by neutralization of TRAIL. These results indicated a substantial role of TRAIL as an effector molecule that eliminates developing tumors.

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Figures

Figure 1.

Figure 1.

Effect of anti-TRAIL mAb on development of MCA-induced fibrosarcoma. p53+/− (A) or wild-type (B) B6 mice were inoculated subcutaneously in the hind flank with the indicated amount of MCA. Mice (n = 10 in each group) were administered intraperitoneally with anti-TRAIL mAb (circles) or isotype-matched control rat Ig (squares) every 5 d, and then observed for sarcoma development over the course of 100–200 d. Tumor sizes in p53+/− mice were also recorded over that period and are represented as the mean ± SD of 3–10 mice in each group.

Figure 2.

Figure 2.

Selection of TRAIL-resistant fibrosarcomas in vivo. Cell lines were originated from MCA-induced fibrosarcomas developed in isotype-matched control rat Ig- or anti-TRAIL mAb-treated p53+/− (A) or wild-type (B) B6 mice. Then, their susceptibility to TRAIL-mediated cytotoxicity was determined by an 8 h 51Cr release assay using mTRAIL-transfected 2PK-3 (mTRAIL-2PK3) and mock-transfected 2PK-3 cells as effector cells. Data are represented as the mean ± SD of triplicate samples at an E/T = 10. The cytotoxic activity of mock-transfected 2PK-3 against all tumor cells was <2% (data not shown).

Figure 2.

Figure 2.

Selection of TRAIL-resistant fibrosarcomas in vivo. Cell lines were originated from MCA-induced fibrosarcomas developed in isotype-matched control rat Ig- or anti-TRAIL mAb-treated p53+/− (A) or wild-type (B) B6 mice. Then, their susceptibility to TRAIL-mediated cytotoxicity was determined by an 8 h 51Cr release assay using mTRAIL-transfected 2PK-3 (mTRAIL-2PK3) and mock-transfected 2PK-3 cells as effector cells. Data are represented as the mean ± SD of triplicate samples at an E/T = 10. The cytotoxic activity of mock-transfected 2PK-3 against all tumor cells was <2% (data not shown).

Figure 3.

Figure 3.

Effect of anti-TRAIL mAb on outgrowth of subcutaneously inoculated fibrosarcoma cell lines. (A) Susceptibility of MCA-induced fibrosarcoma cell lines to TRAIL-mediated cytotoxicity. Cytotoxic activity of mTRAIL-transfected 2PK-3 (mTRAIL/2PK-3) and mock-transfected 2PK-3 cells against MCA-induced fibrosarcoma cell lines (MCA-III and MCA-IV) was tested by an 8 h 51Cr release assay. Data are represented as the mean ± SD of triplicate samples at an E/T ratio = 10. (B) The indicated number of MCA-III (white symbols) and MCA-IV (black symbols) cells were inoculated subcutaneously in the hind flank of wild-type B6 mice. Mice were administered intraperitoneally with anti-TRAIL mAb (circles) or isotype-matched control rat Ig (squares) every 5 d. Data are represented as the mean ± SD of five mice in each group.

Figure 4.

Figure 4.

Contribution of TRAIL to NK cell–mediated tumor surveillance. (A) p53+/− B6 mice (n = 10 in each group) were subcutaneously inoculated with 25 μg MCA and treated with isotype-matched control rat Ig (○), anti-TRAIL mAb (•), anti-ASGM1 Ab (▵), or anti-ASGM1 Ab and anti-TRAIL mAb (▴). Mice were observed for sarcoma development over the course of 125 d. (B) Cell lines were originated from MCA-induced fibrosarcomas developed in control Ig-treated or anti-ASGM1 Ab-treated wild-type B6 mice, and their susceptibility to TRAIL-mediated cytotoxicity was determined as described in Fig. 2. Data are represented as the mean ± SD of triplicate samples at an E/T = 10. The cytotoxic activity of mock-transfected 2PK-3 cells against all tumor cells was <2% (data not shown).

Figure 4.

Figure 4.

Contribution of TRAIL to NK cell–mediated tumor surveillance. (A) p53+/− B6 mice (n = 10 in each group) were subcutaneously inoculated with 25 μg MCA and treated with isotype-matched control rat Ig (○), anti-TRAIL mAb (•), anti-ASGM1 Ab (▵), or anti-ASGM1 Ab and anti-TRAIL mAb (▴). Mice were observed for sarcoma development over the course of 125 d. (B) Cell lines were originated from MCA-induced fibrosarcomas developed in control Ig-treated or anti-ASGM1 Ab-treated wild-type B6 mice, and their susceptibility to TRAIL-mediated cytotoxicity was determined as described in Fig. 2. Data are represented as the mean ± SD of triplicate samples at an E/T = 10. The cytotoxic activity of mock-transfected 2PK-3 cells against all tumor cells was <2% (data not shown).

Figure 5.

Figure 5.

Contribution of TRAIL to IFN-γ–mediated tumor surveillance. Groups of 10 wild-type (circles) and IFN-γ-deficient (triangles) B6 mice were inoculated subcutaneously with the indicated amount of MCA, and treated with isotype-matched control rat IgG (white) or anti-TRAIL mAb (black) as described in Fig. 1. Mice were observed weekly for sarcoma development over the course of 180 d.

Figure 6.

Figure 6.

Effect of IFN-γ on susceptibility of MCA-induced fibrosarcoma cells to TRAIL-mediated cytotoxicity. MCA-induced fibrosarcoma cells from control Ig- or anti-TRAIL mAb-treated p53+/− or wild-type mice, control Ig- or anti-ASGM1 Ab-treated wild-type mice, or IFN-γ–deficient mice were preincubated with (solid black bars) or without (gray bars) IFN-γ for 24 h. Then, their susceptibility to TRAIL-mediated cytotoxicity was determined as described in Fig. 2. Data are represented as the mean ± SD of triplicate samples at an E/T = 10. The cytotoxic activity of mock-transfected 2PK-3 cells against all tumor cells was <2% (data not shown).

Figure 7.

Figure 7.

Effect of anti-TRAIL mAb on spontaneous tumor development in p53+/− mice. (A) p53+/− B6 mice were administered intraperitoneally with anti-TRAIL mAb (circles) or isotype-matched control rat Ig (squares) every 5 d starting at 3 wk of age, and then observed for tumor development over the course of 24 mo. Difference between two groups was statistically significant (P < 0.05) as analyzed by unpaired Mann-Whitney U test. (B) Cell lines were originated from spontaneous sarcoma development in isotype-matched control rat Ig- or anti-TRAIL mAb-treated p53+/− mice. Then, their susceptibility to TRAIL-mediated cytotoxicity was determined as described in Fig. 2 after the preincubated with (solid black bars) or without (gray bars) IFN-γ for 24 h. Data are represented as the mean ± SD of triplicate samples at an E/T = 10. The cytotoxic activity of mock-transfected 2PK-3 cells against all tumor cells was <2% (data not shown).

Figure 7.

Figure 7.

Effect of anti-TRAIL mAb on spontaneous tumor development in p53+/− mice. (A) p53+/− B6 mice were administered intraperitoneally with anti-TRAIL mAb (circles) or isotype-matched control rat Ig (squares) every 5 d starting at 3 wk of age, and then observed for tumor development over the course of 24 mo. Difference between two groups was statistically significant (P < 0.05) as analyzed by unpaired Mann-Whitney U test. (B) Cell lines were originated from spontaneous sarcoma development in isotype-matched control rat Ig- or anti-TRAIL mAb-treated p53+/− mice. Then, their susceptibility to TRAIL-mediated cytotoxicity was determined as described in Fig. 2 after the preincubated with (solid black bars) or without (gray bars) IFN-γ for 24 h. Data are represented as the mean ± SD of triplicate samples at an E/T = 10. The cytotoxic activity of mock-transfected 2PK-3 cells against all tumor cells was <2% (data not shown).

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