Functional characterization of OX40 expressed on human CD8+ T cells

Fujita, Tomoko; Ukyo, Naoya; Hori, Tomohide; Uchiyama, Takashi

doi:10.1016/j.imlet.2006.04.001

Cited by 40 publications

(27 citation statements)

References 41 publications

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“…We and others have previously shown that OX40 is expressed on recently activated CD4 and CD8 T cells, and aOX40 treatment leads to enhanced expansion and survival of antigen-activated CD4 and CD8 T cells (1)(2)(3)(4)(8)(9)(10)(11). After systemic aOX40 therapy, there was a dramatic increase in CD8 T cells at the tumor site in the MCA205 sarcoma, EMT6 breast carcinoma and CT26 colorectal carcinoma models (Fig.…”

Section: Resultsmentioning

confidence: 74%

“…Provision of OX40 agonistic antibodies in the absence of a danger signal can replace the adjuvant effect, resulting in enhanced expansion of T cells and increased long-term memory T-cell populations (1). The majority of reports have identified important roles for OX40 in CD4 function (1)(2)(3)(4), although agonistic antibodies to OX40 also have powerful effects on the proliferation, effector function, and long-term survival of CD8 T cells (8)(9)(10)(11).…”

Section: Introductionmentioning

confidence: 99%

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OX40 Agonist Therapy Enhances CD8 Infiltration and Decreases Immune Suppression in the Tumor

et al. 2008

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Acquisition of full T-cell effector function and memory differentiation requires appropriate costimulatory signals, including ligation of the costimulatory molecule OX40 (TNFRSF4, CD134). Tumors often grow despite the presence of tumor-specific T cells and establish an environment with weak costimulation and immune suppression. Administration of OX40 agonists has been shown to significantly increase the survival of tumor-bearing mice and was dependent on the presence of both CD4 and CD8 T cells during tumor-specific priming. To understand how OX40 agonists work in mice with established tumors, we developed a model to study changes in immune cell populations within the tumor environment. We show here that systemic administration of OX40 agonist antibodies increased the proportion of CD8 T cells at the tumor site in three different tumor models. The function of the CD8 T cells at the tumor site was also increased by administration of OX40 agonist antibody, and we observed an increase in the proportion of antigen-specific CD8 T cells within the tumor. Despite decreases in the proportion of T regulatory cells at the tumor site, T regulatory cell function in the spleen was unaffected by OX40 agonist antibody therapy. Interestingly, administration of OX40 agonist antibody caused significant changes in the tumor stroma, including decreased macrophages, myeloid-derived suppressor cells, and decreased expression of transforming growth factor-B. Thus, therapies targeting OX40 dramatically changed the tumor environment by enhancing the infiltration and function of CD8 T cells combined with diminished suppressive influences within the tumor. [Cancer Res 2008;68(13):5206-15]

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Section: Resultsmentioning

confidence: 74%

Section: Introductionmentioning

confidence: 99%

OX40 Agonist Therapy Enhances CD8 Infiltration and Decreases Immune Suppression in the Tumor

et al. 2008

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“…37,38 Furthermore, anti-OX40 has been shown to potentiate antitumor immune responses in multiple in vivo tumor models. 39,40 We treated 8-day tumor-bearing mice with dasatinib or vehicle for 3 days and then administered 2 doses of anti-OX40 antibody on days 10 and 13 ( Figure 4A).…”

Section: Org Frommentioning

confidence: 99%

Antitumor T-cell responses contribute to the effects of dasatinib on c-KIT mutant murine mastocytoma and are potentiated by anti-OX40

Yang

Liu

Peng

et al. 2012

Blood

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Targeted and immune-based therapies are thought to eradicate cancer cells by different mechanisms, and these approaches could possibly complement each other when used in combination. In this study, we report that the in vivo antitumor effects of the c-KIT inhibitor, dasatinib, on the c-KIT mutant P815 mastocytoma tumor were substantially dependent on T cell-mediated immunity. We found that dasatinib treatment significantly decreased levels of Tregs while specifically enhancing tumor antigen-specific T-cell responses. We sought to further enhance this therapy with the addition of anti-OX40 antibody, which is known to pro-

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“…þ and CD8 þ T cells (1)(2)(3). Engagement of OX40 with cognate ligand or soluble agonist enhances T-cell proliferation, survival, and cytokine production by activated T cells (4).…”

Section: Ox40 (Cd134 Tnfrsf4) Is a Member Of The Tnf Receptor (Tnfr)mentioning

confidence: 99%

STAT3 Signaling Is Required for Optimal Regression of Large Established Tumors in Mice Treated with Anti-OX40 and TGFβ Receptor Blockade

Triplett

Tucker

Triplett

et al. 2015

Cancer Immunology Research

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In preclinical tumor models, aOX40 therapy is often successful at treating small tumors, but is less effective once the tumors become large. For a tumor immunotherapy to be successful to cure large tumors, it will most likely require not only an agonist to boost effector T-cell function but also inhibitors of T-cell suppression. In this study, we show that combining aOX40 antibodies with an inhibitor of the TGFb receptor (SM16) synergizes to elicit complete regression of large established MCA205 and CT26 tumors. Evaluation of tumor-infiltrating T cells showed that SM16/aOX40 dual therapy resulted in an increase in proliferating granzyme B þ CD8 T cells, which produced higher levels of IFNg, compared with treatment with either agent alone. We also found that the dual treatment increased pSTAT3 expression in both CD4 and CD8 T cells isolated from tumors. Because others have published that STAT3 signaling is detrimental to T-cell function within the tumor microenvironment, we explored whether deletion of STAT3 in OX40-expressing cells would affect this potent combination therapy. Surprisingly, we found that deletion of STAT3 in OX40-expressing cells decreased the efficacy of this combination therapy, showing that the full therapeutic potential of this treatment depends on STAT3 signaling, most likely in the T cells of tumor-bearing mice. Cancer Immunol Res; 3(5); 526-35. Ó2015 AACR.

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Functional characterization of OX40 expressed on human CD8+ T cells

Cited by 40 publications

References 41 publications

OX40 Agonist Therapy Enhances CD8 Infiltration and Decreases Immune Suppression in the Tumor

OX40 Agonist Therapy Enhances CD8 Infiltration and Decreases Immune Suppression in the Tumor

Antitumor T-cell responses contribute to the effects of dasatinib on c-KIT mutant murine mastocytoma and are potentiated by anti-OX40

STAT3 Signaling Is Required for Optimal Regression of Large Established Tumors in Mice Treated with Anti-OX40 and TGFβ Receptor Blockade

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