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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

MD5-1 induces infiltration of macrophages and DCs in tumor site. Tumor was removed 8 d after tumor inoculation from control Ig-, MD5-1–, or MD5-1– and anti-CD11b mAb (5C6)–treated mice, and then stained with H/E (×5), anti-F4/80 mAb (×10), or anti-CD205 mAb (×10). The marginal region of s.c. tumor is shown. A massive infiltration of F4/80+ macrophages (stained brown) was observed in the marginal region of tumor from MD5-1–treated mice. The arrows are indicated to distinguish CD205+ DCs from nonspecific staining of mast cells. Representative of five tumors in each group.
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fig5: MD5-1 induces infiltration of macrophages and DCs in tumor site. Tumor was removed 8 d after tumor inoculation from control Ig-, MD5-1–, or MD5-1– and anti-CD11b mAb (5C6)–treated mice, and then stained with H/E (×5), anti-F4/80 mAb (×10), or anti-CD205 mAb (×10). The marginal region of s.c. tumor is shown. A massive infiltration of F4/80+ macrophages (stained brown) was observed in the marginal region of tumor from MD5-1–treated mice. The arrows are indicated to distinguish CD205+ DCs from nonspecific staining of mast cells. Representative of five tumors in each group.

Mentions: To confirm the recruitment of macrophages in tumor rejection, we examined the tumor sections by immunohistochemistry. Significantly larger numbers of infiltrating CD11b+ mononuclear cells (unpublished data), including F4/80+ macrophages and CD205+ DCs, were observed at the tumor edge in the MD5-1–treated mice as compared with the control Ig–treated mice (Fig. 5). The MD5-1–induced macrophage and DC infiltration into tumor was almost completely inhibited by the anti-CD11b mAb (5C6) treatment (Fig. 5). These results suggested that the antitumor effect of MD5-1 was mainly mediated by the FcR on macrophages, but did not depend on endogenous perforin, TRAIL, or IFN-γ.


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)

MD5-1 induces infiltration of macrophages and DCs in tumor site. Tumor was removed 8 d after tumor inoculation from control Ig-, MD5-1–, or MD5-1– and anti-CD11b mAb (5C6)–treated mice, and then stained with H/E (×5), anti-F4/80 mAb (×10), or anti-CD205 mAb (×10). The marginal region of s.c. tumor is shown. A massive infiltration of F4/80+ macrophages (stained brown) was observed in the marginal region of tumor from MD5-1–treated mice. The arrows are indicated to distinguish CD205+ DCs from nonspecific staining of mast cells. Representative of five tumors in each group.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2211825&req=5

fig5: MD5-1 induces infiltration of macrophages and DCs in tumor site. Tumor was removed 8 d after tumor inoculation from control Ig-, MD5-1–, or MD5-1– and anti-CD11b mAb (5C6)–treated mice, and then stained with H/E (×5), anti-F4/80 mAb (×10), or anti-CD205 mAb (×10). The marginal region of s.c. tumor is shown. A massive infiltration of F4/80+ macrophages (stained brown) was observed in the marginal region of tumor from MD5-1–treated mice. The arrows are indicated to distinguish CD205+ DCs from nonspecific staining of mast cells. Representative of five tumors in each group.
Mentions: To confirm the recruitment of macrophages in tumor rejection, we examined the tumor sections by immunohistochemistry. Significantly larger numbers of infiltrating CD11b+ mononuclear cells (unpublished data), including F4/80+ macrophages and CD205+ DCs, were observed at the tumor edge in the MD5-1–treated mice as compared with the control Ig–treated mice (Fig. 5). The MD5-1–induced macrophage and DC infiltration into tumor was almost completely inhibited by the anti-CD11b mAb (5C6) treatment (Fig. 5). These results suggested that the antitumor effect of MD5-1 was mainly mediated by the FcR on macrophages, but did not depend on endogenous perforin, TRAIL, or IFN-γ.

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