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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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Induction of tumor-specific T cell memory by MD5-1–mediated tumor rejection. (A) BALB/c mice were inoculated with 4T1 cells and then treated with MD5-1 mAb (▪; n = 25) or control Ig (□; n = 5) (left). Simultaneously to secondary challenge with 4T1 cells, some mice were treated with anti-CD4 mAb (•), anti-CD8 mAb (▴), anti-CD4 and anti-CD8 mAbs (▾), or control Ig (▪) (middle). Naive mice were inoculated with 4T1 cells as the control (□). Irrelevant R331-mock cells were inoculated into 4T1-rejecting mice (♦) or naive mice (⋄) (right). (B) BALB/c (squares) and SCID (circles) mice were inoculated with 4T1 cells and then treated with MD5-1 mAb (solid symbols; n = 25) or control Ig (open symbols; n = 5) (left). 5 wk after the first inoculation, the MD5-1–treated BALB/c (▪) and SCID (•) mice that had rejected 4T1 were secondarily inoculated with 4T1 cells (middle). Naive BALB/c (□) and SCID (○) mice were inoculated with 4T1 cells as the control. 2 d after inoculation of 4T1 cells, some SCID mice were i.v. transferred with splenic T cells from the MD5-1–treated BALB/c mice that had rejected 4T1 (•) or naive BALB/c mice (▵) (right). Naive SCID mice (○) and MD5-1–treated wild-type BALB/c mice that had rejected 4T1 (▪) were inoculated with 4T1 cells as the control. (C) Naive BALB/c mice (▿), MD5-1–treated wild-type BALB/c mice that had rejected live 4T1 (□), BALB/c mice immunized by irradiated 4T1 cells precoated with control Ig (▵), or BALB/c mice immunized by irradiated 4T1 cells precoated with MD5-1 (○) were inoculated with the indicated number of live 4T1 tumor cells. (D) Cytotoxic activity of splenic T cells against 4T1 (left) or R331-mock (right) target cells. Effector splenic T cells were prepared from BALB/c mice that had rejected live 4T1 cells by MD5-1 treatment (□), BALB/c mice that had been immunized by irradiated 4T1 cells precoated with MD5-1 (○) or control Ig (▵), or naive BALB/c mice (▿). All data are represented as the mean ± SE of 5–10 mice. Similar results were obtained in three to five independent experiments.
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fig6: Induction of tumor-specific T cell memory by MD5-1–mediated tumor rejection. (A) BALB/c mice were inoculated with 4T1 cells and then treated with MD5-1 mAb (▪; n = 25) or control Ig (□; n = 5) (left). Simultaneously to secondary challenge with 4T1 cells, some mice were treated with anti-CD4 mAb (•), anti-CD8 mAb (▴), anti-CD4 and anti-CD8 mAbs (▾), or control Ig (▪) (middle). Naive mice were inoculated with 4T1 cells as the control (□). Irrelevant R331-mock cells were inoculated into 4T1-rejecting mice (♦) or naive mice (⋄) (right). (B) BALB/c (squares) and SCID (circles) mice were inoculated with 4T1 cells and then treated with MD5-1 mAb (solid symbols; n = 25) or control Ig (open symbols; n = 5) (left). 5 wk after the first inoculation, the MD5-1–treated BALB/c (▪) and SCID (•) mice that had rejected 4T1 were secondarily inoculated with 4T1 cells (middle). Naive BALB/c (□) and SCID (○) mice were inoculated with 4T1 cells as the control. 2 d after inoculation of 4T1 cells, some SCID mice were i.v. transferred with splenic T cells from the MD5-1–treated BALB/c mice that had rejected 4T1 (•) or naive BALB/c mice (▵) (right). Naive SCID mice (○) and MD5-1–treated wild-type BALB/c mice that had rejected 4T1 (▪) were inoculated with 4T1 cells as the control. (C) Naive BALB/c mice (▿), MD5-1–treated wild-type BALB/c mice that had rejected live 4T1 (□), BALB/c mice immunized by irradiated 4T1 cells precoated with control Ig (▵), or BALB/c mice immunized by irradiated 4T1 cells precoated with MD5-1 (○) were inoculated with the indicated number of live 4T1 tumor cells. (D) Cytotoxic activity of splenic T cells against 4T1 (left) or R331-mock (right) target cells. Effector splenic T cells were prepared from BALB/c mice that had rejected live 4T1 cells by MD5-1 treatment (□), BALB/c mice that had been immunized by irradiated 4T1 cells precoated with MD5-1 (○) or control Ig (▵), or naive BALB/c mice (▿). All data are represented as the mean ± SE of 5–10 mice. Similar results were obtained in three to five independent experiments.

Mentions: Given the accumulation of APCs such as macrophages and DCs in the tumor, we next examined whether eradication of primary tumors by the MD5-1 treatment could induce tumor-specific T cell immunity. MD5-1 administration afforded complete rejection of low doses of 4T1 cells in wild-type BALB/c mice (Fig. 6 A, left). When rechallenged with 4T1 or R331-mock cells on the opposite flank, these mice rejected 4T1 cells (Fig. 6 A, middle), but not R331-mock cells (Fig. 6 A, right). Depletion of either CD8+ T cells or CD4+ T cells abrogated the secondary rejection, although some suppression of tumor growth was still observed in the CD4+ T cell–depleted mice (Fig. 6 A, middle). In contrast, BALB/c mice preimmunized with the same number of irradiated 4T1 cells did not reject the secondary challenge with live 4T1 cells (unpublished data).


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)

Induction of tumor-specific T cell memory by MD5-1–mediated tumor rejection. (A) BALB/c mice were inoculated with 4T1 cells and then treated with MD5-1 mAb (▪; n = 25) or control Ig (□; n = 5) (left). Simultaneously to secondary challenge with 4T1 cells, some mice were treated with anti-CD4 mAb (•), anti-CD8 mAb (▴), anti-CD4 and anti-CD8 mAbs (▾), or control Ig (▪) (middle). Naive mice were inoculated with 4T1 cells as the control (□). Irrelevant R331-mock cells were inoculated into 4T1-rejecting mice (♦) or naive mice (⋄) (right). (B) BALB/c (squares) and SCID (circles) mice were inoculated with 4T1 cells and then treated with MD5-1 mAb (solid symbols; n = 25) or control Ig (open symbols; n = 5) (left). 5 wk after the first inoculation, the MD5-1–treated BALB/c (▪) and SCID (•) mice that had rejected 4T1 were secondarily inoculated with 4T1 cells (middle). Naive BALB/c (□) and SCID (○) mice were inoculated with 4T1 cells as the control. 2 d after inoculation of 4T1 cells, some SCID mice were i.v. transferred with splenic T cells from the MD5-1–treated BALB/c mice that had rejected 4T1 (•) or naive BALB/c mice (▵) (right). Naive SCID mice (○) and MD5-1–treated wild-type BALB/c mice that had rejected 4T1 (▪) were inoculated with 4T1 cells as the control. (C) Naive BALB/c mice (▿), MD5-1–treated wild-type BALB/c mice that had rejected live 4T1 (□), BALB/c mice immunized by irradiated 4T1 cells precoated with control Ig (▵), or BALB/c mice immunized by irradiated 4T1 cells precoated with MD5-1 (○) were inoculated with the indicated number of live 4T1 tumor cells. (D) Cytotoxic activity of splenic T cells against 4T1 (left) or R331-mock (right) target cells. Effector splenic T cells were prepared from BALB/c mice that had rejected live 4T1 cells by MD5-1 treatment (□), BALB/c mice that had been immunized by irradiated 4T1 cells precoated with MD5-1 (○) or control Ig (▵), or naive BALB/c mice (▿). All data are represented as the mean ± SE of 5–10 mice. Similar results were obtained in three to five independent experiments.
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Related In: Results  -  Collection

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fig6: Induction of tumor-specific T cell memory by MD5-1–mediated tumor rejection. (A) BALB/c mice were inoculated with 4T1 cells and then treated with MD5-1 mAb (▪; n = 25) or control Ig (□; n = 5) (left). Simultaneously to secondary challenge with 4T1 cells, some mice were treated with anti-CD4 mAb (•), anti-CD8 mAb (▴), anti-CD4 and anti-CD8 mAbs (▾), or control Ig (▪) (middle). Naive mice were inoculated with 4T1 cells as the control (□). Irrelevant R331-mock cells were inoculated into 4T1-rejecting mice (♦) or naive mice (⋄) (right). (B) BALB/c (squares) and SCID (circles) mice were inoculated with 4T1 cells and then treated with MD5-1 mAb (solid symbols; n = 25) or control Ig (open symbols; n = 5) (left). 5 wk after the first inoculation, the MD5-1–treated BALB/c (▪) and SCID (•) mice that had rejected 4T1 were secondarily inoculated with 4T1 cells (middle). Naive BALB/c (□) and SCID (○) mice were inoculated with 4T1 cells as the control. 2 d after inoculation of 4T1 cells, some SCID mice were i.v. transferred with splenic T cells from the MD5-1–treated BALB/c mice that had rejected 4T1 (•) or naive BALB/c mice (▵) (right). Naive SCID mice (○) and MD5-1–treated wild-type BALB/c mice that had rejected 4T1 (▪) were inoculated with 4T1 cells as the control. (C) Naive BALB/c mice (▿), MD5-1–treated wild-type BALB/c mice that had rejected live 4T1 (□), BALB/c mice immunized by irradiated 4T1 cells precoated with control Ig (▵), or BALB/c mice immunized by irradiated 4T1 cells precoated with MD5-1 (○) were inoculated with the indicated number of live 4T1 tumor cells. (D) Cytotoxic activity of splenic T cells against 4T1 (left) or R331-mock (right) target cells. Effector splenic T cells were prepared from BALB/c mice that had rejected live 4T1 cells by MD5-1 treatment (□), BALB/c mice that had been immunized by irradiated 4T1 cells precoated with MD5-1 (○) or control Ig (▵), or naive BALB/c mice (▿). All data are represented as the mean ± SE of 5–10 mice. Similar results were obtained in three to five independent experiments.
Mentions: Given the accumulation of APCs such as macrophages and DCs in the tumor, we next examined whether eradication of primary tumors by the MD5-1 treatment could induce tumor-specific T cell immunity. MD5-1 administration afforded complete rejection of low doses of 4T1 cells in wild-type BALB/c mice (Fig. 6 A, left). When rechallenged with 4T1 or R331-mock cells on the opposite flank, these mice rejected 4T1 cells (Fig. 6 A, middle), but not R331-mock cells (Fig. 6 A, right). Depletion of either CD8+ T cells or CD4+ T cells abrogated the secondary rejection, although some suppression of tumor growth was still observed in the CD4+ T cell–depleted mice (Fig. 6 A, middle). In contrast, BALB/c mice preimmunized with the same number of irradiated 4T1 cells did not reject the secondary challenge with live 4T1 cells (unpublished data).

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