Combined stimulation of TLR9 and 4.1BB augments Trp2 peptide vaccine-mediated melanoma rejection by increasing Ag-specific CTL activity and infiltration into tumor sites

Sin, Jeong-Im; Kim, Heon; Ahn, Euri; Jeon, Yong Hwan; Park, Won Sun; Lee, Sang‐Yeul; Kwon, Byungsuk

doi:10.1016/j.canlet.2012.11.045

Cited by 27 publications

(17 citation statements)

References 40 publications

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“…Sin et al . (51) have recently demonstrated that a combination of anti-4-1BB antibodies with Trp2 peptides, in the presence of TLR9 agonists, increased the antitumor effect from 0% to 75%. In an orthotropic model of metastatic colon carcinoma established in the liver of mice, combination therapy with IL-12 and stimulatory anti-4-1BB led to CD8 + T and NK cell-dependent tumor regression (52).…”

Section: Anti-4-1bb Combination Therapy With Other Anti-cancer Agentsmentioning

confidence: 99%

4-1BB (CD137), an inducible costimulatory receptor, as a specific target for cancer therapy

2014

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Although considerable progress has been made in understanding how tumors evade immune surveillance, measures to counter the same have not kept pace with the advances made in designing effective strategies. 4-1BB (CD137; TNFRS9), an activation-induced costimulatory molecule, is an important regulator of immune responses. Targeting 4-1BB or its natural ligand 4-1BB ligand (4-1BBL) has important implications in many clinical conditions, including cancer. In-depth analysis revealed that 4-1BB-mediated anti-cancer effects are based on its ability to induce activation of cytotoxic T lymphocytes (CTL), and among others, high amounts of IFN-γ. In this review, we will discuss the various aspects of 4-1BB-mediated anti-tumor responses, the basis of such responses, and future directions. [BMB Reports 2014; 47(3): 122-129]

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Section: Anti-4-1bb Combination Therapy With Other Anti-cancer Agentsmentioning

confidence: 99%

4-1BB (CD137), an inducible costimulatory receptor, as a specific target for cancer therapy

2014

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“…Agonistic anti-4-1BB Abs have been reported to enhance tumor rejection and increase tumor-specific cytotoxicity in numerous studies [21]–[23]. In our recent study, large established subcutaneous B16 melanomas were effectively controlled by combined therapy using Trp2 peptide vaccines with a Toll-like receptor 9 agonist (CpG-ODN) and anti-4-1BB Abs [24]. In this context, it can be speculated that combined stimulation through IL-2, IL-15 and 4-1BB receptors may enhance Ag-specific CD8+ CTL responses induced by E7 DNA vaccines, thereby conferring more effective tumor control in an HPV E7-expressing tumor model.…”

Section: Introductionmentioning

confidence: 96%

Combined Stimulation of IL-2 and 4-1BB Receptors Augments the Antitumor Activity of E7 DNA Vaccines by Increasing Ag-Specific CTL Responses

Kim¹,

Kwon

Sin

2013

PLoS ONE

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Human papillomavirus (HPV) infection is a major cause of cervical cancer. Here, we investigate whether concurrent therapy using HPV E7 DNA vaccines (pE7) plus IL-2 vs. IL-15 cDNA and anti-4-1BB Abs might augment antitumor activity against established tumors. IL-2 cDNA was slightly better than IL-15 cDNA as a pE7 adjuvant. Co-delivery of pE7+IL-2 cDNA increased tumor cure rates from 7% to 27%, whereas co-delivery of pE7+IL-2 cDNA with anti-4-1BB Abs increased tumor cure rates from 27% to 67% and elicited long-term memory responses. This increased activity was concomitant with increased induction of Ag-specific CTL activity and IFN-γ responses, but not with Ag-specific IgG production. Moreover, the combined stimulation of IL-2 and 4-1BB receptors with rIL-2 and anti-4-1BB Abs resulted in enhanced production of IFN-γ from Ag-specific CD8+ T cells. However, this effect was abolished by treatment with anti-IL-2 Abs and 4-1BB-Fc, suggesting that the observed effect was IL-2- and anti-4-1BB Ab-specific. A similar result was also obtained for Ag-specific CTL activity. Thus, these studies demonstrate that combined stimulation through the IL-2 and 4-1BB receptors augments the Ag-specific CD8+ CTL responses induced by pE7, increasing tumor cure rates and long-term antitumor immune memory. These findings may have implications for the design of DNA-based therapeutic vaccines against cancer.

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“…4T1.2 cells expressing human erbB-2 (4T1.2/HER2 cells), a breast cancer cell line also originating from BALB/c mice, were kindly provided by P. K. Darcy (Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia). TC-1 and MC32 cells originate from C57BL/6 mice and have been previously tested [29, 32, 43, 44]. The tumor cells were maintained in cDMEM medium (supplemented with 10% fetal bovine serum [FBS], 1% L-glutamine and 1% penicillin/streptomycin), except for the TC-1 cells, which were grown in cRPMI medium (supplemented with 10% FBS, 1% L-glutamine and 1% penicillin/streptomycin) containing 400 μg/ml of G418.…”

Section: Methodsmentioning

confidence: 99%

“…on the indicated days. A hybridoma cell line (clones 2.43) was purchased from the American Type Culture Collection (Manassas, VA), and anti-CD8 IgG was obtained as previously described [44]. Control rat IgG was purchased from Sigma-Aldrich.…”

Section: Methodsmentioning

confidence: 99%

Tumor regression is mediated via the induction of HER263-71- specific CD8+ CTL activity in a 4T1.2/HER2 tumor model: no involvement of CD80 in tumor control

2017

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In the CT26/HER2 and 4T1.2/HER2 tumor models, CT26/HER2 cells form tumors that continue to grow, whereas 4T1.2/HER2 cells form tumors that eventually regress. Here, we investigated the differences in the behaviors of these two cell lines. When immune cells from 4T1.2/HER2 tumor-bearing animals were stimulated with HER2 class I peptides, they displayed a 2-fold increase in IFN-γ levels, in response to the peptides, HER263–71 and HER2342–350. In contrast, extremely high levels of antigen-non-specific IFN-γ production were observed with immune cells and sera from CT26/HER2 tumor-bearing mice. However, IFN-γ had no effect on tumor progression in the CT26/HER2 model, as determined by an IFN-γ knockout assay. 4T1.2/HER2 tumor-bearing mice displayed CTL activity in response to HER263–71 but not to HER2342–350, whereas no such induction was observed in CT26/HER2 tumor-bearing mice. When 4T1.2/HER2 cell-challenged mice were depleted of CD8+ T cells, they lost their tumor-regressing activity, suggesting an antitumor role of HER263–71-specific CD8+ CTLs in the control of this tumor type. CT26/HER2 cells also expressed CD80. However, CD80-transfected 4T1.2/HER2 and CD80-non-expressing CT26/HER2 cells failed to alter their tumorigenicity, suggesting no role of CD80 in tumor control. Despite increased levels of myeloid-derived suppressor cells in the tumor, they were not associated with tumor progression in the CT26/HER2 model, as determined by a cell depletion assay. Overall, these data show that, contrary to CT26/HER2 tumors, 4T1.2/HER2 tumors regress via the induction of HER263–71-specific CD8+ CTLs and that CD80 is not associated with the regression of these tumors.

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Combined stimulation of TLR9 and 4.1BB augments Trp2 peptide vaccine-mediated melanoma rejection by increasing Ag-specific CTL activity and infiltration into tumor sites

Cited by 27 publications

References 40 publications

4-1BB (CD137), an inducible costimulatory receptor, as a specific target for cancer therapy

4-1BB (CD137), an inducible costimulatory receptor, as a specific target for cancer therapy

Combined Stimulation of IL-2 and 4-1BB Receptors Augments the Antitumor Activity of E7 DNA Vaccines by Increasing Ag-Specific CTL Responses

Tumor regression is mediated via the induction of HER263-71- specific CD8+ CTL activity in a 4T1.2/HER2 tumor model: no involvement of CD80 in tumor control

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