Tumor Progression Despite Efficient Tumor Antigen Cross-Presentation and Effective “Arming” of Tumor Antigen-Specific CTL

Nelson, Delia J.; Mukherjee, Sutapa; Bundell, Christine; Fisher, Scott; Hagen, Deborah van; Robinson, Bruce

doi:10.4049/jimmunol.166.9.5557

Cited by 61 publications

(47 citation statements)

References 44 publications

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Section: Discussionmentioning

confidence: 99%

“…In the case of EG7 cells, it must be taken into account that OVA is secreted to the cellular milieu [49] and that tumor exosomes may also participate in antigen transfer [50].…”

Section: Discussionmentioning

confidence: 99%

“…39: 2424 The similarity of such protein to a real tumor antigenic sequence is debatable, but allows demonstration of proof-of-concept [4,47,48]. In the case of EG7 cells, it must be taken into account that OVA is secreted to the cellular milieu [49] and that tumor exosomes may also participate in antigen transfer [50].Our experiments required an immunogenic tumor sensitive to anti-CD137 mAb treatment as monotherapy. Administration of agonistic anti-CD137 mAb induced the eradication of well-established EG7-OVA-derived tumors by a CD8 1 T-cell-dependent mechanism that correlated with an enhanced in vivo CTL activity against the immunodominant tumor antigen.…”

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In vivo depletion of DC impairs the anti‐tumor effect of agonistic anti‐CD137 mAb

et al. 2009

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Anti-CD137 mAb are capable of inducing tumor rejection in several syngeneic murine tumor models and are undergoing clinical trials for cancer. The anti-tumor effect involves costimulation of tumor-specific CD8 1 T cells. Whether antigen cross-presenting DC are required for the efficacy of anti-CD137 mAb treatment has never been examined. Here we show that the administration of anti-CD137 mAb eradicates EG7-OVA tumors by a strictly CD8b 1 T-celldependent mechanism that correlates with increased CTL activity. Ex vivo analyses to determine the identity of the draining lymph node cell type responsible for tumor antigen crosspresentation revealed that CD11c 1 cells, most likely DC, are the main players in this tumor model. A minute number of tumor cells, revealed by the presence of OVA cDNA, reach tumordraining lymph nodes. Direct antigen presentation by tumor cells themselves also participates in anti-OVA CTL induction. Using CD11c diphtheria toxin receptor-green fluorescent protein-C57BL/6 BM chimeric mice, which allow for sustained ablation of DC with diphtheria toxin, we confirmed the involvement of DC in tumor antigen cross-presentation in CTL induction against OVA [257][258][259][260][261][262][263][264] epitope and in the antitumor efficacy induced by anti-CD137 mAb.Key words: CD137 (4-1BB) . Cross-priming . CTL . DC . Tumor immunity Supporting Information available online Introduction CD137, also known as 4-1BB, is a TNF-receptor family costimulatory molecule originally identified on activated T cells [1]. Its natural ligand CD137L is found on APC, including B cells, macrophages, and DC [2]. In the presence of TCR engagement, signaling through CD137 leads to increased T-cell proliferation, cytokine production, and prolonged CD8 1 T-cell survival in vitro [2]. Administration of agonistic anti-CD137 mAb either alone or following peptide vaccination is capable of inducing the eradication of established tumors in several transplantable tumor models [3,4]. This anti-tumor effect is dependent on CD8 1 T cells that show increases in tumor-specific cytotoxic activity and associated IFN-g production [3,4]. Recent studies have demonstrated that the activity of anti-CD137 mAb treatment is also dependent on their ability to enhance the survival of CD8 1 CTL, and on the prevention/reversal of established anergy [5][6][7]. In addition, antigen-independent anti-CD137 mAb effects have been described for memory T cells, and CD137 seems to be an Ã These authors contributed equally to this work.ÃÃ These authors share equal senior authorship. 2424important player in the differentiation of memory cells [8][9][10]. CD137 can also be expressed by activated NK cells [11], myeloid leukocytes [12] including DC [13,14], and tumor endothelial cells [15]. However, the role of CD137 molecules expressed on these non-T cells during tumor immunotherapy remains undefined [13,16].As naïve CTL do not express CD137 on their surface, susceptibility to CD137 triggering depends on prior up-regulation of this receptor [5]. This requires antigen rec...

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Section: Discussionmentioning

confidence: 99%

“…In the case of EG7 cells, it must be taken into account that OVA is secreted to the cellular milieu [49] and that tumor exosomes may also participate in antigen transfer [50].…”

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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In vivo depletion of DC impairs the anti‐tumor effect of agonistic anti‐CD137 mAb

et al. 2009

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“…Thus, many tumors are simply ignored by the immune system because they do not function as professional APCs (1). Tolerance induction (2), incomplete "arming" (3), and impaired functional activity of tumor-infiltrating T cells (4) have also been demonstrated. Stroma surrounding cancer cells may play a critical role in preventing antitumor immunity (5).…”

Section: Lack Of Effector Cell Function and Altered Tetramer Binding mentioning

confidence: 99%

“…3 The gp33 epitope represents a strong CTL epitope of LCMV (11) and was selected as a model Ag because it allows tracing of gp33/ tumor-specific CD8 T cells in normal mice using MHC class I tetramers complexed with the gp33 peptide (12,13). The gp33 epitope has been used as a tumor-associated model Ag before and, depending on the tumor cell type and Ag expression levels, T cell priming (14,15), spontaneous tumor regression (16), ignorance (17)(18)(19), or tolerance induction (20) has been observed.…”

Section: Lack Of Effector Cell Function and Altered Tetramer Binding mentioning

confidence: 99%

Lack of Effector Cell Function and Altered Tetramer Binding of Tumor-Infiltrating Lymphocytes

Blohm

Roth

Brommer

et al. 2002

The Journal of Immunology

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Tumor-specific CD8 T cell responses to MCA102 fibrosarcoma cells expressing the cytotoxic T cell epitope gp33 from lymphocytic choriomeningitis virus were studied. MCA102gp33 tumors grew progressively in C57BL/6 mice, despite induction of peripheral gp33-tetramer+ T cells that were capable of mediating antiviral protection, specific cell rejection, and concomitant tumor immunity. MCA102gp33 tumors were infiltrated with a high number (∼20%) of CD11b+CD11c− macrophage-phenotype cells that were able to cross-present the gp33 epitope to T cells. Tumor-infiltrating CD8 T cells exhibited a highly activated phenotype but lacked effector cell function. Strikingly, a significant portion of tumor-infiltrating lymphocytes expressed TCRs specific for gp33 but bound MHC tetramers only after cell purification and a 24-h resting period in vitro. The phenomenon of “tetramer-negative T cells” was not restricted to tumor-infiltrating lymphocytes from MCA102gp33 tumors, but was also observed when Ag-specific T cells derived from an environment with high Ag load were analyzed ex vivo. Thus, using a novel tumor model, allowing us to trace tumor-specific T cells at the single cell level in vivo, we demonstrate that the tumor microenvironment is able to alter the functional activity of T cells infiltrating the tumor mass.

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The CCL5/CCR5 axis promotes interleukin‐6 production in human synovial fibroblasts

Tang

Hsu

Fong

2010

Arthritis & Rheumatism

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Objective. CCL5 (RANTES) was originally identified as a product of activated T cells and plays a crucial role in the inflammatory response. This study was undertaken to investigate the intracellular signaling pathways involved in CCL5-induced interleukin-6 (IL-6) production in human synovial fibroblasts.Methods. CCL5-mediated IL-6 expression was assessed by quantitative polymerase chain reaction and enzyme-linked immunosorbent assay. The mechanisms of action of CCL5 in different signaling pathways were studied using Western blotting. Knockdown of CCR5 and protein kinase C␦ (PKC␦) protein was achieved by transfection of small interfering RNA (siRNA). Chromatin immunoprecipitation assays were used to study in vivo binding of c-Jun to the IL-6 promoter. Transient transfection was used to examine IL-6 and activator protein 1 (AP-1) activity.Results. Osteoarthritis synovial fibroblasts (OASFs) showed significant expression of CCL5 and CCR5, and expression was higher than that in normal synovial fibroblasts. Stimulation of OASFs with CCL5 induced concentration-and time-dependent increases in IL-6 production. CCL5-mediated IL-6 production was attenuated by CCR5 monoclonal antibody, CCR5 inhibitor ( Conclusion. The present results suggest that the interaction between CCL5 and CCR5 increases IL-6 production in human synovial fibroblasts via the PKC␦/ c-Src/c-Jun and AP-1 signaling pathways.

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Tumor Progression Despite Efficient Tumor Antigen Cross-Presentation and Effective “Arming” of Tumor Antigen-Specific CTL

Cited by 61 publications

References 44 publications

In vivo depletion of DC impairs the anti‐tumor effect of agonistic anti‐CD137 mAb

In vivo depletion of DC impairs the anti‐tumor effect of agonistic anti‐CD137 mAb

Lack of Effector Cell Function and Altered Tetramer Binding of Tumor-Infiltrating Lymphocytes

The CCL5/CCR5 axis promotes interleukin‐6 production in human synovial fibroblasts

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