4-1BB signaling beyond T cells

Vinay, Dass S.; Kwon, Byoung S.

doi:10.1038/cmi.2010.82

Cited by 124 publications

(110 citation statements)

References 37 publications

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“…This difference, however, was not always seen. The small decrease of phospho-S6-expressing host (CD45.1 -) cells seen in the 4-1BB-raptor conjugate-treated mice may correspond to a small fraction of non-CD8 + T cells that also express 4-1BB (46,47), reflecting the lack of complete specificity of this targeting protocol. We further evaluated the specificity of aptamer-targeted mTORC1 inhibition by cotransferring mice with OT-I cells together with EL-4 T lymphoma cells that can be readily distinguished by flow cytometry ( Figure 2C).…”

Section: Resultsmentioning

confidence: 99%

“…While 4-1BB expression is highly restricted, it is also upregulated on activated conventional CD4 + T cells, Foxp3 + Tregs, activated NK cells, CD40-stimulated mature DCs (reviewed in ref. 46), and on proliferating ECs (47). Given that 4-1BB signaling (46,47) and mTOR inhibition (30,31) can exert immune-potentiating or immunosuppressive effects, the positive and negative contributions of 4-1BB-targeted mTOR inhibition in other cells to the protective antitumor immune responses shown in Figure 5B and Figure 6, A, C, and D remain to be determined.…”

Section: Adoptive Transfer Of Ot-i Cells Into Mice and Treatment Withmentioning

confidence: 99%

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Aptamer-targeted inhibition of mTOR in T cells enhances antitumor immunity

Berezhnoy¹,

Castro²,

Levay³

et al. 2013

J. Clin. Invest.

112

104

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Recent studies have underscored the importance of memory T cells in mediating protective immunity against pathogens and cancer. Pharmacological inhibition of regulators that mediate T cell differentiation promotes the differentiation of activated CD8 + T cells into memory cells. Nonetheless, pharmacological agents have broad targets and can induce undesirable immunosuppressive effects. Here, we tested the hypothesis that aptamer-targeted siRNA inhibition of mTOR complex 1 (mTORC1) function in CD8 + T cells can enhance their differentiation into memory T cells and potentiate antitumor immunity more effectively than the pharmacologic inhibitor rapamycin. To specifically target activated cells, we conjugated an siRNA targeting the mTORC1 component raptor to an aptamer that binds 4-1BB, a costimulatory molecule that is expressed on CD8 + T cells following TCR stimulation. We found that systemic administration of the 4-1BB aptamer-raptor siRNA to mice downregulated mTORC1 activity in the majority of CD8 + T cells, leading to the generation of a potent memory response that exhibited cytotoxic effector functions and enhanced vaccine-induced protective immunity in tumor-bearing mice. In contrast, while treatment with the general mTORC1 inhibitor rapamycin also enhanced antigen-activated CD8 + T cell persistence, the cytotoxic effector functions of the reactivated memory cells were reduced and the alloreactivity of DCs was diminished. Consistent with the immunological findings, mice treated with rapamycin, but not with 4-1BB aptamer-raptor siRNA, failed to reject a subsequent tumor challenge.

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Section: Resultsmentioning

confidence: 99%

Section: Adoptive Transfer Of Ot-i Cells Into Mice and Treatment Withmentioning

confidence: 99%

Aptamer-targeted inhibition of mTOR in T cells enhances antitumor immunity

Berezhnoy¹,

Castro²,

Levay³

et al. 2013

J. Clin. Invest.

112

104

View full text Add to dashboard Cite

show abstract

“…Functional 4-1BB expression has also been observed on myeloid cells, such as monocytes, neutrophils, mast cells, and eosinophils (6). Once expressed, 4-1BB binds to a high-affinity 4-1BB ligand (4-1BBL) that is present on a variety of APCs, including DCs, B cells, and macrophages (3)(4)(5).…”

Section: -1bb-4-1bb Ligandmentioning

confidence: 99%

Immunotherapy of Cancer with 4-1BB

Vinay

Kwon²

2012

Molecular Cancer Therapeutics

163

130

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4-1BB (CD137), a member of the TNF receptor superfamily, is an activation-induced T-cell costimulatory molecule. Signaling via 4-1BB upregulates survival genes, enhances cell division, induces cytokine production, and prevents activation-induced cell death in T cells. The importance of the 4-1BB pathway has been underscored in a number of diseases, including cancer. Growing evidence indicates that anti-4-1BB monoclonal antibodies possess strong antitumor properties, which in turn are the result of their powerful CD8þ T-cell activating, IFN-g producing, and cytolytic marker-inducing capabilities. In addition, combination therapy of anti-4-1BB with other anticancer agents, such as radiation, has robust tumor-regressing abilities against nonimmunogenic or poorly immunogenic tumors. Furthermore, the adoptive transfer of ex vivo anti-4-1BB-activated CD8þ T cells from previously tumor-treated animals efficiently inhibits progression of tumors in recipient mice that have been inoculated with fresh tumors. In addition, targeting of tumors with variants of 4-1BBL directed against 4-1BB also have potent antitumor effects. Currently, a humanized anti-4-1BB is in clinical trials in patients with solid tumors, including melanoma, renal carcinoma, and ovarian cancer, and so far seems to have a favorable toxicity profile. In this review, we discuss the basis of the therapeutic potential of targeting the 4-1BB-4-1BBL pathway in cancer treatment.

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“…This protein binds to the receptor 4-1BB, generating a co-stimulatory signal for T cell activation and expansion (17,18). Although 4-1BB is typically expressed on activated but not resting T-cells (19,20), this receptor has also been detected on NK cells (21). The functional domain of 4-1BBL is located in the extracellular domain (22,23), and soluble 4-1BBL has no activity compared with the natural membranebound form (24).…”

Section: Introductionmentioning

confidence: 99%

Expansion of NK cells from PBMCs using immobilized 4-1BBL and interleukin-21

Liu

et al. 2015

International Journal of Oncology

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Abstract. Adoptive transfer of NK cells has been widely applied clinically for cancer immunotherapy. However, the difficulties to obtain a large number of activated NK cells impede the successful application of such therapy. In the present study, we implemented a novel method involving the use of immobilized human 4-1BBL and interleukin-21 to amplify NK cells from the peripheral blood mononuclear cells (PBMCs) of healthy donors. Following stimulation for 21 days, we achieved considerable expansion of NK cells with high purity and strong cytotoxicity. This is the first time solid phase cytokines were used to augment NK cells, and this method has the advantage of no need to introduce feeder cells, without prior purification of NK cells and it effectively stimulated and expanded NK cells. The strategy of cell proliferation and activation could lead to a safer and more effective application of NK cells clinically.

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4-1BB signaling beyond T cells

Cited by 124 publications

References 37 publications

Aptamer-targeted inhibition of mTOR in T cells enhances antitumor immunity

Aptamer-targeted inhibition of mTOR in T cells enhances antitumor immunity

Immunotherapy of Cancer with 4-1BB

Expansion of NK cells from PBMCs using immobilized 4-1BBL and interleukin-21

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