Induction of Tumor-specific T Cell Immunity by Anti-DR5 Antibody Therapy

Takeda, Kazuyoshi; Yamaguchi, Noriko; Akiba, Hisaya; Kojima, Yuko; Hayakawa, Yoshihiro; Tanner, Jane E.; Sayers, Thomas J.; Seki, Naoko; Okumura, Ko; Yagita, Hideo; Smyth, Mark J.

doi:10.1084/jem.20031457

Cited by 190 publications

(210 citation statements)

References 58 publications

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“…Blocking CD11b ϩ cell infiltration partially inhibited the early antitumor effect of the combination treatment, whereas NK cell depletion had no effect. Previous experiments in another model of mouse mammary carcinoma have shown that MD5-1 activity completely depended on a combination of CD11b ϩ cell infiltration and NK cells, and that Fc␥R expression was essential (26). We now need to create Fc␥R-deficient erbB2 transgenic mice and explore the role of FcR in single-and dual-mAb therapy, as well as examine which CD11b ϩ cells (neutrophils and/or monocytes/macrophages) and CD11b Ϫ innate cells are potentially suppressing tumor growth.…”

Section: Discussionmentioning

confidence: 96%

Antibodies targeted to TRAIL receptor-2 and ErbB-2 synergize in vivo and induce an antitumor immune response

Stagg

Sharkey

Pommey

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Despite the development of human epidermal growth factor receptor-2 (ErbB-2/HER2)-targeted therapies, there remains an unmet medical need for breast cancer patients with ErbB-2 overexpression. We investigated the therapeutic activity of an agonist mAb to mouse tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor-2 (DR5) against ErbB2-driven breast cancer. Established tumors in BALB/c transgenic mice expressing a constitutively active ErbB-2/neuT were treated with anti-DR5 mAb and/or anti-ErbB-2 mAb and monitored for tumor progression. Treatment with anti-DR5 or anti-ErbB2 mAb as single agents significantly delayed tumor growth, although all tumors eventually progressed. Remarkably, treatment with a combination of anti-DR5 and anti-ErbB-2 mAbs induced complete response in a majority of mice. In vivo blockade of CD11b ؉ cells, but not natural killer cell depletion, significantly abrogated the early antitumor response. Notably, depletion of CD8 ؉ T cells provoked primary and secondary tumor relapse, revealing the induction of antitumor immunity by the combination treatment. Combined therapy with anti-DR5 and anti-ErbB-2 mAbs further significantly suppressed the growth of advanced spontaneous tumors in ErbB-2/neuT transgenic mice, even when treatment was delayed until tumors were palpable. We thus demonstrated that the combination of anti-DR5 and anti-ErbB2 mAbs might be an effective form of treatment for ErbB-2-overexpressing breast cancer.apoptosis ͉ breast cancer ͉ herceptin ͉ immunity H uman epidermal growth factor receptor-2 (ErbB-2/HER2) is overexpressed in 20-30% of patients with breast cancer and is associated with a poor prognosis (1). The use of trastuzumab (Herceptin; Genentech), a mAb that blocks the activity of ErbB-2, in combination with chemotherapy has been associated with an increased median survival in patients with advanced ErbB-2-positive breast cancer (2-4). In addition to its inhibitory effect on ErbB-2 signaling, trastuzumab mediates its therapeutic effect through the recruitment of immune cells such as monocytes and natural killer (NK) cells (1, 5). Accordingly, trastuzumab-like mAb unable to bind Fc receptors has less therapeutic activity (6), and complete or partial remission induced by trastuzumab correlates with higher antibody-dependent cell cytotoxicity (7-9).Although the development of trastuzumab constitute a major advance in the treatment of ErbB-2-overexpressing breast cancer, there remains an unmet medical need for new therapies. Proapoptotic receptor agonists (PARAs), including recombinant Apo2L/ tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and mAbs, have now emerged as promising anticancer agents (10, 11). PARAs exploit the enhanced susceptibility of cancer cells versus nontransformed cells to TRAIL-mediated apoptosis. Activation of TRAIL-R1 (DR4) or TRAIL-R2 (DR5) triggers the formation of a death-inducing signaling complex (DISC) that activates caspase-8. In some cells (type I), the activation of the ensuing caspase cascade is sufficient t...

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Section: Discussionmentioning

confidence: 96%

Antibodies targeted to TRAIL receptor-2 and ErbB-2 synergize in vivo and induce an antitumor immune response

Stagg

Sharkey

Pommey

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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“…TRAIL is critically involved in anti-cancer surveillance by immune cells (Takeda et al, 2001(Takeda et al, , 2004Schmaltz et al, 2002) and also has the ability to trigger apoptosis in a cell autonomous way, in a variety of tumor cell lines, but not in most normal cells (Walczak et al, 1999;Wang and El-Deiry, 2003). Importantly, TRAIL À/À mice display an increased susceptibility to tumor initiation and metastasis Sedger et al, 2002), highlighting the importance of TRAIL in the defense against tumors.…”

Section: Introductionmentioning

confidence: 99%

BCR–ABL-mediated upregulation of PRAME is responsible for knocking down TRAIL in CML patients

et al. 2010

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“…TRAIL is a TNF-like cytokine that selectively induces apoptosis in many tumor cells, but not in normal cells. Administration of recombinant TRAIL or antibodies against TR2 in several experimental tumor models exhibited potent antitumor activity with minimal hepatic toxicity (2)(3)(4)(5)(6). Moreover, recombinant TRAIL or agonist TRAIL receptor antibody often synergizes with chemotherapy or radiation to induce tumor-cell apoptosis (7)(8)(9)(10).…”

mentioning

confidence: 99%

Preligand assembly domain-mediated ligand-independent association between TRAIL receptor 4 (TR4) and TR2 regulates TRAIL-induced apoptosis

Clancy

Mruk²,

Archer³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a cytokine with potential therapeutic value against cancers because of its selective cytotoxicity to many transformed, but not normal, cells. The ''decoy receptors'' TRAIL-R3 (TR3) and TRAIL-R4 (TR4) were believed to negatively regulate TRAIL-induced cytotoxicity by competing for ligand binding with TRAIL-R1 (TR1) and TRAIL-R2 (TR2). Here, we show that inhibition of TRAILinduced apoptosis by TR4 critically depends on its association with TR2 via the NH 2-terminal preligand assembly domain overlapping the first partial cysteine-rich domain of both receptors. By contrast, ligand binding by TR4 is dispensable for its apoptosis inhibitory function, thereby excluding the possibility that TR4 was a ''decoy'' to inhibit apoptosis by binding up TRAIL. In primary CD8 ؉ T cells, which express only TR2 and TR4 and are resistant to TRAIL-induced apoptosis, stimulation with phorbol myristate acetate abrogated the ligand-independent interaction between TR2 and TR4 and enhanced their sensitivity to TRAIL-induced apoptosis. Hence, whereas most TNF receptors normally form only homotrimeric complexes, the preligand assembly domains in TR2 and TR4 permit mixed complex formation as a means to regulate apoptosis induction. We propose that TR4 is a ''regulatory'' rather than ''decoy'' receptor that inhibits apoptosis signaling by TRAIL through this previously uncharacterized ligand-independent mechanism. decoy receptors T he regulation of cell death by members of the TNF family plays a critical role in immune function and homeostasis (1). TRAIL is a TNF-like cytokine that selectively induces apoptosis in many tumor cells, but not in normal cells. Administration of recombinant TRAIL or antibodies against TR2 in several experimental tumor models exhibited potent antitumor activity with minimal hepatic toxicity (2-6). Moreover, recombinant TRAIL or agonist TRAIL receptor antibody often synergizes with chemotherapy or radiation to induce tumor-cell apoptosis (7-10). This unique property of TRAIL has prompted many to vaunt it as a potential therapeutic agent against malignant diseases. Despite its potency against tumor cells, the physiological function of TRAIL is largely unknown, although some reports have implicated TRAIL to be involved in tumor surveillance (11), target cell killing by various immune effector cells (12,13), and the regulation of innate immune responses (14).TRAIL binds to five distinct TNF receptor (TNFR)-like receptors, TR1 (TRAIL-R1͞DR4), TR2 (TRAIL-R2͞DR5͞ Killer͞Trick), TR3 (TRAIL-R3͞DcR1͞LIT͞TRID), TR4 (TRAIL-R4͞DcR2͞TRUNDD), and the soluble receptor osteoprotegerin (OPG). OPG is a soluble receptor that also binds another TNF-like cytokine called TRANCE͞RANK-L and may have a more prominent role in bone and myeloid cell development than in regulating TRAIL-induced apoptosis. The four membrane-anchored TRAIL receptors contain two complete cysteine-rich domains (CRDs) for ligand binding that are preceded at the NH 2 termini by a highly conserved...

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Induction of Tumor-specific T Cell Immunity by Anti-DR5 Antibody Therapy

Cited by 190 publications

References 58 publications

Antibodies targeted to TRAIL receptor-2 and ErbB-2 synergize in vivo and induce an antitumor immune response

Antibodies targeted to TRAIL receptor-2 and ErbB-2 synergize in vivo and induce an antitumor immune response

BCR–ABL-mediated upregulation of PRAME is responsible for knocking down TRAIL in CML patients

Preligand assembly domain-mediated ligand-independent association between TRAIL receptor 4 (TR4) and TR2 regulates TRAIL-induced apoptosis

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