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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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Related in: MedlinePlus

Induction of perforin- and FasL-mediated T cell cytotoxicity that can also eliminate TRAIL-resistant variants. (A) BALB/c mice were inoculated with R331-mock (squares) or R331-FLIP (circles) cells, and then treated with MD5-1 mAb (solid symbols; n = 20) or control Ig (open symbols; n = 5) (left). The cured mice were secondarily challenged with R331-mock (▪) or R331-FLIP (•) cells (middle). Naive mice were inoculated with R331-mock (□) or R331-FLIP (○) cells, and the mice preimmunized by irradiated R331-mock cells were inoculated with R331-mock cells (▵) as the controls (middle). Simultaneously to the secondary challenge with R331-mock cells, some mice were treated with anti-CD8 mAb (▵), anti-CD4 and anti-CD8 mAbs (▿), or control Ig (□) (right). (B) R331-FLIP cells were inoculated into the left flank (•) at the indicated time point after R331-mock cell inoculation into the right flank (▪) and commencement of MD5-1 treatment on day 0. As a control, R331-FLIP cells were inoculated into naive mice (○) at the same time as the R331-FLIP inoculation into the treated mice. (C) BALB/c mice that had rejected R331-mock by MD5-1 treatment were secondarily challenged with the indicated number of R331-mock or R331-FLIP cells (○). Naive mice were inoculated with the same numbers of R331-mock or R331-FLIP cells and treated with MD5-1 (▪) or control Ig (□) for comparison. (D) Wild-type (squares) or perforin−/− (circles) BALB/c mice were inoculated with R331-mock cells, and then treated with MD5-1 mAb (solid symbols; n = 20) or control Ig (open symbols; n = 5) (left). The cured mice were secondarily challenged with R331-mock cells. Simultaneously to the secondary challenge, some wild-type (middle) and perforin−/− (right) mice were treated with anti-FasL neutralizing mAb (○), anti-TRAIL neutralizing mAb (▵), anti-FasL and anti-TRAIL mAbs (▿), or control Ig (□). Naive wild-type or perforin−/− mice were inoculated with the same number of R331-mock cells as a control (⋄). All data are represented as the mean ± SE of 5–10 mice. Similar results were obtained in two independent experiments.
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fig7: Induction of perforin- and FasL-mediated T cell cytotoxicity that can also eliminate TRAIL-resistant variants. (A) BALB/c mice were inoculated with R331-mock (squares) or R331-FLIP (circles) cells, and then treated with MD5-1 mAb (solid symbols; n = 20) or control Ig (open symbols; n = 5) (left). The cured mice were secondarily challenged with R331-mock (▪) or R331-FLIP (•) cells (middle). Naive mice were inoculated with R331-mock (□) or R331-FLIP (○) cells, and the mice preimmunized by irradiated R331-mock cells were inoculated with R331-mock cells (▵) as the controls (middle). Simultaneously to the secondary challenge with R331-mock cells, some mice were treated with anti-CD8 mAb (▵), anti-CD4 and anti-CD8 mAbs (▿), or control Ig (□) (right). (B) R331-FLIP cells were inoculated into the left flank (•) at the indicated time point after R331-mock cell inoculation into the right flank (▪) and commencement of MD5-1 treatment on day 0. As a control, R331-FLIP cells were inoculated into naive mice (○) at the same time as the R331-FLIP inoculation into the treated mice. (C) BALB/c mice that had rejected R331-mock by MD5-1 treatment were secondarily challenged with the indicated number of R331-mock or R331-FLIP cells (○). Naive mice were inoculated with the same numbers of R331-mock or R331-FLIP cells and treated with MD5-1 (▪) or control Ig (□) for comparison. (D) Wild-type (squares) or perforin−/− (circles) BALB/c mice were inoculated with R331-mock cells, and then treated with MD5-1 mAb (solid symbols; n = 20) or control Ig (open symbols; n = 5) (left). The cured mice were secondarily challenged with R331-mock cells. Simultaneously to the secondary challenge, some wild-type (middle) and perforin−/− (right) mice were treated with anti-FasL neutralizing mAb (○), anti-TRAIL neutralizing mAb (▵), anti-FasL and anti-TRAIL mAbs (▿), or control Ig (□). Naive wild-type or perforin−/− mice were inoculated with the same number of R331-mock cells as a control (⋄). All data are represented as the mean ± SE of 5–10 mice. Similar results were obtained in two independent experiments.

Mentions: Next, we examined whether eradication of primary R331 tumors by MD5-1 treatment enabled the induction of R331-specific T cell immunity. Administration of MD5-1 resulted in complete rejection of 104 R331-mock cells, but not R331-FLIP cells, in BALB/c mice (Fig. 7 A, left). Notably, when rechallenged with R331-mock or R331-FLIP, these mice rejected not only R331-mock, but also R331-FLIP cells (Fig. 7 A, middle). A rechallenge with irrelevant 4T1 tumor cells was not rejected in these mice (unpublished data). In contrast, BALB/c mice preimmunized with 50-fold greater number of irradiated R331-mock cells did not reject the secondary challenge with live R331-mock cells. Depletion of CD8+ T cells abrogated the secondary rejection of both R331-mock (Fig. 7 A, right) and R331-FLIP (unpublished data). These results indicated that the MD5-1–mediated primary rejection of R331-mock cells induced CD8+ T cell–mediated immunity that could also eradicate MD5-1–resistant R331-FLIP cells.


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 perforin- and FasL-mediated T cell cytotoxicity that can also eliminate TRAIL-resistant variants. (A) BALB/c mice were inoculated with R331-mock (squares) or R331-FLIP (circles) cells, and then treated with MD5-1 mAb (solid symbols; n = 20) or control Ig (open symbols; n = 5) (left). The cured mice were secondarily challenged with R331-mock (▪) or R331-FLIP (•) cells (middle). Naive mice were inoculated with R331-mock (□) or R331-FLIP (○) cells, and the mice preimmunized by irradiated R331-mock cells were inoculated with R331-mock cells (▵) as the controls (middle). Simultaneously to the secondary challenge with R331-mock cells, some mice were treated with anti-CD8 mAb (▵), anti-CD4 and anti-CD8 mAbs (▿), or control Ig (□) (right). (B) R331-FLIP cells were inoculated into the left flank (•) at the indicated time point after R331-mock cell inoculation into the right flank (▪) and commencement of MD5-1 treatment on day 0. As a control, R331-FLIP cells were inoculated into naive mice (○) at the same time as the R331-FLIP inoculation into the treated mice. (C) BALB/c mice that had rejected R331-mock by MD5-1 treatment were secondarily challenged with the indicated number of R331-mock or R331-FLIP cells (○). Naive mice were inoculated with the same numbers of R331-mock or R331-FLIP cells and treated with MD5-1 (▪) or control Ig (□) for comparison. (D) Wild-type (squares) or perforin−/− (circles) BALB/c mice were inoculated with R331-mock cells, and then treated with MD5-1 mAb (solid symbols; n = 20) or control Ig (open symbols; n = 5) (left). The cured mice were secondarily challenged with R331-mock cells. Simultaneously to the secondary challenge, some wild-type (middle) and perforin−/− (right) mice were treated with anti-FasL neutralizing mAb (○), anti-TRAIL neutralizing mAb (▵), anti-FasL and anti-TRAIL mAbs (▿), or control Ig (□). Naive wild-type or perforin−/− mice were inoculated with the same number of R331-mock cells as a control (⋄). All data are represented as the mean ± SE of 5–10 mice. Similar results were obtained in two independent experiments.
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Related In: Results  -  Collection

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fig7: Induction of perforin- and FasL-mediated T cell cytotoxicity that can also eliminate TRAIL-resistant variants. (A) BALB/c mice were inoculated with R331-mock (squares) or R331-FLIP (circles) cells, and then treated with MD5-1 mAb (solid symbols; n = 20) or control Ig (open symbols; n = 5) (left). The cured mice were secondarily challenged with R331-mock (▪) or R331-FLIP (•) cells (middle). Naive mice were inoculated with R331-mock (□) or R331-FLIP (○) cells, and the mice preimmunized by irradiated R331-mock cells were inoculated with R331-mock cells (▵) as the controls (middle). Simultaneously to the secondary challenge with R331-mock cells, some mice were treated with anti-CD8 mAb (▵), anti-CD4 and anti-CD8 mAbs (▿), or control Ig (□) (right). (B) R331-FLIP cells were inoculated into the left flank (•) at the indicated time point after R331-mock cell inoculation into the right flank (▪) and commencement of MD5-1 treatment on day 0. As a control, R331-FLIP cells were inoculated into naive mice (○) at the same time as the R331-FLIP inoculation into the treated mice. (C) BALB/c mice that had rejected R331-mock by MD5-1 treatment were secondarily challenged with the indicated number of R331-mock or R331-FLIP cells (○). Naive mice were inoculated with the same numbers of R331-mock or R331-FLIP cells and treated with MD5-1 (▪) or control Ig (□) for comparison. (D) Wild-type (squares) or perforin−/− (circles) BALB/c mice were inoculated with R331-mock cells, and then treated with MD5-1 mAb (solid symbols; n = 20) or control Ig (open symbols; n = 5) (left). The cured mice were secondarily challenged with R331-mock cells. Simultaneously to the secondary challenge, some wild-type (middle) and perforin−/− (right) mice were treated with anti-FasL neutralizing mAb (○), anti-TRAIL neutralizing mAb (▵), anti-FasL and anti-TRAIL mAbs (▿), or control Ig (□). Naive wild-type or perforin−/− mice were inoculated with the same number of R331-mock cells as a control (⋄). All data are represented as the mean ± SE of 5–10 mice. Similar results were obtained in two independent experiments.
Mentions: Next, we examined whether eradication of primary R331 tumors by MD5-1 treatment enabled the induction of R331-specific T cell immunity. Administration of MD5-1 resulted in complete rejection of 104 R331-mock cells, but not R331-FLIP cells, in BALB/c mice (Fig. 7 A, left). Notably, when rechallenged with R331-mock or R331-FLIP, these mice rejected not only R331-mock, but also R331-FLIP cells (Fig. 7 A, middle). A rechallenge with irrelevant 4T1 tumor cells was not rejected in these mice (unpublished data). In contrast, BALB/c mice preimmunized with 50-fold greater number of irradiated R331-mock cells did not reject the secondary challenge with live R331-mock cells. Depletion of CD8+ T cells abrogated the secondary rejection of both R331-mock (Fig. 7 A, right) and R331-FLIP (unpublished data). These results indicated that the MD5-1–mediated primary rejection of R331-mock cells induced CD8+ T cell–mediated immunity that could also eradicate MD5-1–resistant R331-FLIP cells.

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