Shift from Systemic to Site-Specific Memory by Tumor-Targeted IL-2

Schrama, David; Xiang, Rong; Eggert, Andreas O.; Andersen, Mads Hald; Pedersen, Lars Østergaard; Kämpgen, Eckhart; Schumacher, Ton N.; Reisfeld, Ralph R.; Becker, J. C.

doi:10.4049/jimmunol.172.10.5843

Cited by 14 publications

(9 citation statements)

References 36 publications

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“…This measure actually boosted the therapeutic effect of a TRP‐2 vaccine, resulting in the partial or complete regression of established tumors. However, it also interfered severely with the development of a protective, systemic memory (54). Indeed, high local concentrations of IL‐2 at the dermal/s.c.…”

Section: Syngeneic Transplantation Modelssupporting

confidence: 90%

Mouse models for melanoma: a personal perspective

Becker

Houben

Schrama

et al. 2010

Experimental Dermatology

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Complex biological processes often require in vivo analysis, and many important research advances have been made using mice as a model for the study of various biological systems. Cutaneous melanomas are tumors originating from skin melanocytes, which are present in hair follicles, and interfollicular epidermal and dermal layers. Until recently, mouse melanoma models were largely based on transplantation models, i.e. transplantation of either syngeneic or xenogeneic melanoma cells into wild type or genetically modified animals. More recently, however, the use of novel technologies specifically modifying the genome allows for the generation of mouse strains, which may develop spontaneous melanoma. Nevertheless, it should be kept in mind that animal models provide only an approximation of reality in humans. In this review, we will discuss a representative selection of currently available transplantation and transgenic melanoma models; despite the fact that this selection will be biased by personal experience, we are confident to demonstrate how the use of mouse melanoma models facilitates translational research in several biomedical disciplines.

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Section: Syngeneic Transplantation Modelssupporting

confidence: 90%

Mouse models for melanoma: a personal perspective

Becker

Houben

Schrama

et al. 2010

Experimental Dermatology

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“…CD8 ? T cells did not express increased levels of CD44 (compared with PBS controls), suggesting that IL-2 did not increase the induce effector memory T cells, which were site-specific, rather than central memory T cells [37]. Furthermore, others have shown that local IL-2 can induce a systemic response leading to the destruction of distant metastases [32,33,38].…”

Section: Discussionmentioning

confidence: 95%

Intratumoral interleukin-2/agonist CD40 antibody drives CD4+-independent resolution of treated-tumors and CD4+-dependent systemic and memory responses

Jackaman

Nelson

2011

Cancer Immunol Immunother

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Targeting interleukin-2 (IL-2) and/or agonist anti-CD40 antibody (Ab) into tumors represents an effective vaccination strategy that avoids systemic toxicity and resolves treated-site tumors. Here, we examined IL-2 and/or anti-CD40 Ab-driven local versus systemic T cell function and the installation of T cell memory. Single tumor studies showed that IL-2 induced a potent CD4+ and CD8+ T cell response that was limited to the draining lymph node and treated-site tumor, and lymph node tumor-specific CD8+ T cells did not upregulate CD44. A two-tumor model showed that while IL-2-treated-site tumors resolved, distal tumors continued to grow, implying limited systemic immunity. In contrast, anti-CD40 Ab treatment with or without IL-2 expanded the systemic T cell response to non-draining lymph nodes, and distal tumors resolved. Tumor-specific T cells in lymph nodes of anti-CD40 Ab ± IL-2-treated mice upregulated CD44, demonstrating activation and transition to effector/memory migratory cells. While CD40-activated CD4+ T cells were not required for eradicating treated-site tumors, they, plus CD8+ T cells, were crucial for removing distal tumors. Rechallenge/depletion experiments showed that the effector/memory phase required the presence of previously CD40/IL-2-activated CD4+ and CD8+ T cells to prevent recurrence. These novel findings show that different T cell effector mechanisms can operate for the eradication of local treated-site tumors versus untreated distal tumors and that signaling through CD40 generates a whole of body, effector/memory CD4+ and CD8+ T cell response that is amplified and prolonged via IL-2. Thus, successful immunotherapy needs to generate collaborating CD4+ and CD8+ T cells for a complete long-term protective cure.

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“…B78-D14 melanoma is derived from B16F0, a cell line with C57BL/6 background, by transfection of genes coding for β-1,4-N-acetylgalactosaminyltransferase and α-sialyltransferase, inducing the expression of the disialogangliosides GD2 and GD3 (16,17). B16-EpCAM is a B16 variant expressing the EpCAM antigen (14).…”

Section: Cell Lines Preparation Of T Cells and Generation Of Dcsmentioning

confidence: 99%

Potential of the Trifunctional Bispecific Antibody Surek Depends on Dendritic Cells: Rationale for a New Approach of Tumor Immunotherapy

Eißler

Mysliwietz

Deppisch

et al. 2013

Mol Med

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Trifunctional bispecific antibodies (trAbs) used in tumor immunotherapy have the unique ability to recruit T cells toward antigens on the tumor cell surface and, moreover, to activate accessory cells through their immunoglobulin Fc region interacting with activating Fcγ receptors. This scenario gives rise to additional costimulatory signals required for T cell-mediated tumor cell destruction and induction of an immunologic memory. Here we show in an in vitro system that most effective trAb-dependent T-cell activation and tumor cell elimination are achieved in the presence of dendritic cells (DCs). On the basis of these findings, we devise a novel approach of cancer immunotherapy that combines the specific advantages of trAbs with those of DC-based vaccination. Simultaneous delivery of trAbs and in vitro differentiated DCs resulted in a markedly improved tumor rejection in a murine melanoma model compared with monotherapy.

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Shift from Systemic to Site-Specific Memory by Tumor-Targeted IL-2

Cited by 14 publications

References 36 publications

Mouse models for melanoma: a personal perspective

Mouse models for melanoma: a personal perspective

Intratumoral interleukin-2/agonist CD40 antibody drives CD4+-independent resolution of treated-tumors and CD4+-dependent systemic and memory responses

Potential of the Trifunctional Bispecific Antibody Surek Depends on Dendritic Cells: Rationale for a New Approach of Tumor Immunotherapy

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