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Induction of tumor-specific T cell immunity by anti-DR5 antibody therapy.

Takeda K, Yamaguchi N, Akiba H, Kojima Y, Hayakawa Y, Tanner JE, Sayers TJ, Seki N, Okumura K, Yagita H, Smyth MJ - J. Exp. Med. (2004)

Bottom Line: Here we report that a monoclonal antibody (mAb) against the mouse TRAIL receptor, DR5, exhibited potent antitumor effects against TRAIL-sensitive tumor cells in vivo by recruiting Fc receptor-expressing innate immune cells, with no apparent systemic toxicity.Administration of the agonistic anti-DR5 mAb also significantly inhibited experimental and spontaneous tumor metastases.These results suggested that the antibody-based therapy targeting DR5 is an efficient strategy not only to eliminate TRAIL-sensitive tumor cells, but also to induce tumor-specific T cell memory that affords a long-term protection from tumor recurrence.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, Juntendo University School of Medicine, 2-1-1 Hongo, Bukyou-ku, Tokyo 113-8421, Japan. ktakeda@med.juntendo.ac.jp

ABSTRACT
Because tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) preferentially induces apoptosis in tumor cells and plays a critical role in tumor surveillance, its receptor is an attractive target for antibody-mediated tumor therapy. Here we report that a monoclonal antibody (mAb) against the mouse TRAIL receptor, DR5, exhibited potent antitumor effects against TRAIL-sensitive tumor cells in vivo by recruiting Fc receptor-expressing innate immune cells, with no apparent systemic toxicity. Administration of the agonistic anti-DR5 mAb also significantly inhibited experimental and spontaneous tumor metastases. Notably, the anti-DR5 mAb-mediated tumor rejection by innate immune cells efficiently evoked tumor-specific T cell immunity that could also eradicate TRAIL-resistant variants. These results suggested that the antibody-based therapy targeting DR5 is an efficient strategy not only to eliminate TRAIL-sensitive tumor cells, but also to induce tumor-specific T cell memory that affords a long-term protection from tumor recurrence.

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Contribution of macrophages and NK cells to tumoricidal effect of MD5-1. SCID mice (A) or wild-type BALB/c mice (B) were s.c. inoculated with 4T1 cells, and wild-type BALB/c mice (C) were s.c. inoculated with R331-mock cells. The mice were then treated with MD5-1 (solid symbols) or control Ig (open symbols). Some groups of mice were treated with anti-ASGM1 Ab (triangles), anti-CD11b mAb (circles), or control Igs (squares). (D) Wild-type BALB/c mice were s.c. inoculated with 4T1 cells. The mice were then treated with MD5-1 from day 0 (▪), 15 (•), or 25 (▴). One group of mice was treated with control Ig from day 0 (□) as the control. (E) Wild-type (squares), TRAIL−/− (circles), perforin−/− (triangles), and IFN-γ−/− (upside down triangles) BALB/c mice were s.c. inoculated with R331-mock cells. The mice were then treated with MD5-1 (solid symbols) or control Ig (open symbols). (F) Wild-type (squares), FcRγ−/− (circles), or FcγRII−/− (triangles) BALB/c mice were s.c. inoculated with 4T1 cells. The mice were then treated with MD5-1 (solid symbols) or control Ig (open symbols). Some groups of wild-type mice were treated with both anti-ASGM1 Ab and anti-CD11b mAb (upside down triangles). All data are represented as the mean ± SE of 5–10 mice. Similar results were obtained in two or three independent experiments.
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fig4: Contribution of macrophages and NK cells to tumoricidal effect of MD5-1. SCID mice (A) or wild-type BALB/c mice (B) were s.c. inoculated with 4T1 cells, and wild-type BALB/c mice (C) were s.c. inoculated with R331-mock cells. The mice were then treated with MD5-1 (solid symbols) or control Ig (open symbols). Some groups of mice were treated with anti-ASGM1 Ab (triangles), anti-CD11b mAb (circles), or control Igs (squares). (D) Wild-type BALB/c mice were s.c. inoculated with 4T1 cells. The mice were then treated with MD5-1 from day 0 (▪), 15 (•), or 25 (▴). One group of mice was treated with control Ig from day 0 (□) as the control. (E) Wild-type (squares), TRAIL−/− (circles), perforin−/− (triangles), and IFN-γ−/− (upside down triangles) BALB/c mice were s.c. inoculated with R331-mock cells. The mice were then treated with MD5-1 (solid symbols) or control Ig (open symbols). (F) Wild-type (squares), FcRγ−/− (circles), or FcγRII−/− (triangles) BALB/c mice were s.c. inoculated with 4T1 cells. The mice were then treated with MD5-1 (solid symbols) or control Ig (open symbols). Some groups of wild-type mice were treated with both anti-ASGM1 Ab and anti-CD11b mAb (upside down triangles). All data are represented as the mean ± SE of 5–10 mice. Similar results were obtained in two or three independent experiments.

Mentions: Administration of MD5-1 substantially inhibited s.c. growth of 4T1 tumors in both SCID (Fig. 4 A) and wild-type BALB/c (Fig. 4 B) mice. Depletion of NK cells by the anti-ASGM1 Ab treatment, but not administration of anti-CD11b mAb (5C6) that inhibits the recruitment of macrophages (34), significantly enhanced 4T1 tumor growth in the control Ig–treated mice, indicating a substantial contribution of NK cells, but not macrophages, to the natural suppression of 4T1 tumor growth. In contrast, the tumoricidal effect of MD5-1 was mostly abrogated by anti-CD11b treatment, but only weakly by NK cell depletion. In the case of R331-mock cells, NK cell depletion did not affect the natural protection, but significantly impaired the tumoricidal effect of MD5-1 (Fig. 4 C). Again, the anti-CD11b treatment mostly abrogated the effect of MD5-1. We also examined the effect of MD5-1 against established tumors. The MD5-1 treatment commencing on day 15 (tumor size was ∼10 mm2) or 25 (tumor size ∼35 mm2) still significantly inhibited the growth of 4T1, although the MD5-1 treatment starting on day 0 was most effective (Fig. 4 D).


Induction of tumor-specific T cell immunity by anti-DR5 antibody therapy.

Takeda K, Yamaguchi N, Akiba H, Kojima Y, Hayakawa Y, Tanner JE, Sayers TJ, Seki N, Okumura K, Yagita H, Smyth MJ - J. Exp. Med. (2004)

Contribution of macrophages and NK cells to tumoricidal effect of MD5-1. SCID mice (A) or wild-type BALB/c mice (B) were s.c. inoculated with 4T1 cells, and wild-type BALB/c mice (C) were s.c. inoculated with R331-mock cells. The mice were then treated with MD5-1 (solid symbols) or control Ig (open symbols). Some groups of mice were treated with anti-ASGM1 Ab (triangles), anti-CD11b mAb (circles), or control Igs (squares). (D) Wild-type BALB/c mice were s.c. inoculated with 4T1 cells. The mice were then treated with MD5-1 from day 0 (▪), 15 (•), or 25 (▴). One group of mice was treated with control Ig from day 0 (□) as the control. (E) Wild-type (squares), TRAIL−/− (circles), perforin−/− (triangles), and IFN-γ−/− (upside down triangles) BALB/c mice were s.c. inoculated with R331-mock cells. The mice were then treated with MD5-1 (solid symbols) or control Ig (open symbols). (F) Wild-type (squares), FcRγ−/− (circles), or FcγRII−/− (triangles) BALB/c mice were s.c. inoculated with 4T1 cells. The mice were then treated with MD5-1 (solid symbols) or control Ig (open symbols). Some groups of wild-type mice were treated with both anti-ASGM1 Ab and anti-CD11b mAb (upside down triangles). All data are represented as the mean ± SE of 5–10 mice. Similar results were obtained in two or three independent experiments.
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Related In: Results  -  Collection

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fig4: Contribution of macrophages and NK cells to tumoricidal effect of MD5-1. SCID mice (A) or wild-type BALB/c mice (B) were s.c. inoculated with 4T1 cells, and wild-type BALB/c mice (C) were s.c. inoculated with R331-mock cells. The mice were then treated with MD5-1 (solid symbols) or control Ig (open symbols). Some groups of mice were treated with anti-ASGM1 Ab (triangles), anti-CD11b mAb (circles), or control Igs (squares). (D) Wild-type BALB/c mice were s.c. inoculated with 4T1 cells. The mice were then treated with MD5-1 from day 0 (▪), 15 (•), or 25 (▴). One group of mice was treated with control Ig from day 0 (□) as the control. (E) Wild-type (squares), TRAIL−/− (circles), perforin−/− (triangles), and IFN-γ−/− (upside down triangles) BALB/c mice were s.c. inoculated with R331-mock cells. The mice were then treated with MD5-1 (solid symbols) or control Ig (open symbols). (F) Wild-type (squares), FcRγ−/− (circles), or FcγRII−/− (triangles) BALB/c mice were s.c. inoculated with 4T1 cells. The mice were then treated with MD5-1 (solid symbols) or control Ig (open symbols). Some groups of wild-type mice were treated with both anti-ASGM1 Ab and anti-CD11b mAb (upside down triangles). All data are represented as the mean ± SE of 5–10 mice. Similar results were obtained in two or three independent experiments.
Mentions: Administration of MD5-1 substantially inhibited s.c. growth of 4T1 tumors in both SCID (Fig. 4 A) and wild-type BALB/c (Fig. 4 B) mice. Depletion of NK cells by the anti-ASGM1 Ab treatment, but not administration of anti-CD11b mAb (5C6) that inhibits the recruitment of macrophages (34), significantly enhanced 4T1 tumor growth in the control Ig–treated mice, indicating a substantial contribution of NK cells, but not macrophages, to the natural suppression of 4T1 tumor growth. In contrast, the tumoricidal effect of MD5-1 was mostly abrogated by anti-CD11b treatment, but only weakly by NK cell depletion. In the case of R331-mock cells, NK cell depletion did not affect the natural protection, but significantly impaired the tumoricidal effect of MD5-1 (Fig. 4 C). Again, the anti-CD11b treatment mostly abrogated the effect of MD5-1. We also examined the effect of MD5-1 against established tumors. The MD5-1 treatment commencing on day 15 (tumor size was ∼10 mm2) or 25 (tumor size ∼35 mm2) still significantly inhibited the growth of 4T1, although the MD5-1 treatment starting on day 0 was most effective (Fig. 4 D).

Bottom Line: Here we report that a monoclonal antibody (mAb) against the mouse TRAIL receptor, DR5, exhibited potent antitumor effects against TRAIL-sensitive tumor cells in vivo by recruiting Fc receptor-expressing innate immune cells, with no apparent systemic toxicity.Administration of the agonistic anti-DR5 mAb also significantly inhibited experimental and spontaneous tumor metastases.These results suggested that the antibody-based therapy targeting DR5 is an efficient strategy not only to eliminate TRAIL-sensitive tumor cells, but also to induce tumor-specific T cell memory that affords a long-term protection from tumor recurrence.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, Juntendo University School of Medicine, 2-1-1 Hongo, Bukyou-ku, Tokyo 113-8421, Japan. ktakeda@med.juntendo.ac.jp

ABSTRACT
Because tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) preferentially induces apoptosis in tumor cells and plays a critical role in tumor surveillance, its receptor is an attractive target for antibody-mediated tumor therapy. Here we report that a monoclonal antibody (mAb) against the mouse TRAIL receptor, DR5, exhibited potent antitumor effects against TRAIL-sensitive tumor cells in vivo by recruiting Fc receptor-expressing innate immune cells, with no apparent systemic toxicity. Administration of the agonistic anti-DR5 mAb also significantly inhibited experimental and spontaneous tumor metastases. Notably, the anti-DR5 mAb-mediated tumor rejection by innate immune cells efficiently evoked tumor-specific T cell immunity that could also eradicate TRAIL-resistant variants. These results suggested that the antibody-based therapy targeting DR5 is an efficient strategy not only to eliminate TRAIL-sensitive tumor cells, but also to induce tumor-specific T cell memory that affords a long-term protection from tumor recurrence.

Show MeSH
Related in: MedlinePlus