Combinational FLt3 Ligand and Granulocyte Macrophage Colony-Stimulating Factor Treatment Promotes Enhanced Tumor Infiltration by Dendritic Cells and Antitumor CD8+ T-Cell Cross-priming but Is Ineffective as a Therapy

Berhanu, Aklile; Huang, Jian; Alber, Sean; Watkins, Simon C.; Storkus, Walter J.

doi:10.1158/0008-5472.can-05-2384

Cited by 27 publications

(33 citation statements)

References 46 publications

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“…Recently, it was reported that combination treatment of mice bearing established tumors with FltL3 and GM-CSF proteins resulted in the recruitment of large numbers of tumorinfiltrating DC and induction of a CD8 þ T-cell-mediated immune response. 36 Mouse splenic DC could be expanded by intramuscular delivery of either Flt3L or GM-CSF cDNA. 11 However, a more potent T-cell proliferation was observed in the mixed lymphocyte reaction when stimulator DC originated from mice treated with Flt3L cDNA, compared Figure 7 Induction of cell-mediated immunity in mice vaccinated with pN-neu combined with pFLAG or pFL/pGM.…”

Section: Discussionmentioning

confidence: 99%

Coexpression of Flt3 ligand and GM-CSF genes modulates immune responses induced by HER2/neu DNA vaccine

Hsu

Shieh

et al. 2007

Cancer Gene Ther

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DNA vaccine and dendritic cells (DCs)-based vaccine have emerged as promising strategies for cancer immunotherapy. Fms-like tyrosine kinase 3-ligand (Flt3L) and granulocyte-macrophage-colony-stimulating factor (GM-CSF) have been exploited for the expansion of DC. It was reported previously that combination of plasmid encoding GM-CSF with HER2/neu DNA vaccine induced predominantly CD4þ T-cell-mediated antitumor immune response. In this study, we investigated the modulation of immune responses by murine Flt3L and GM-CSF, which acted as genetic adjuvants in the forms of bicistronic (pFLAG) and monocistronic (pFL and pGM) plasmids for HER2/neu DNA vaccine (pN-neu). Coexpression of Flt3L and GM-CSF significantly enhanced maturation and antigen-presentation abilities of splenic DC. Increased numbers of infiltrating DC at the immunization site, higher interferon-g production, and enhanced cytolytic activities by splenocytes were prominent in mice vaccinated with pN-neu in conjunction with pFLAG. Importantly, a potent CD8 þ T-cell-mediated antitumor immunity against bladder tumors naturally overexpressing HER2/neu was induced in the vaccinated mice. Collectively, our results indicate that murine Flt3L and GM-CSF genes coexpressed by a bicistronic plasmid modulate the class of immune responses and may be superior to those codelivered by two separate monocistronic plasmids as the genetic adjuvants for HER2/neu DNA vaccine.

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Section: Discussionmentioning

confidence: 99%

Coexpression of Flt3 ligand and GM-CSF genes modulates immune responses induced by HER2/neu DNA vaccine

Hsu

Shieh

et al. 2007

Cancer Gene Ther

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“…In an earlier study, we observed that the treatment of mice bearing syngeneic CMS4 sarcomas with rFLt3 ligand (rFL) plus recombinant GM-CSF (rGM-CSF) resulted in the markedly enhanced cross-priming of anti-CMS4 CD8 ϩ T cells in vivo (26). However, these responses yielded no meaningful impact on tumor growth, despite the infiltration of significant numbers of tumorspecific CD8 ϩ T cells into tumor lesions.…”

Section: T He Cd8mentioning

confidence: 99%

“…CMS4 sarcoma (H-2 d ) cells were cultured, and s.c. tumors were established and monitored for growth in syngeneic BALB/cJ mice, as previously described (26).…”

Section: Tumor Establishmentmentioning

confidence: 99%

“…Mice were injected s.c. in the scruff of the neck with 20 g each of rFL and rGM-CSF for five consecutive days in a total volume each of 100 l of PBS, as we have previously shown this protocol to optimize the number of tumor-infiltrating DC (dendritic cells) (TIDC) and consequent priming of anti-CMS4 CD8 ϩ T cells in vivo (26). To deplete CD4 ϩ and/or CD8 ϩ T cells, mice were injected i.p.…”

Section: Combinational Cytokine Therapy and Ab Depletionsmentioning

confidence: 99%

“…Single-cell suspensions were obtained from resected spleens and tumors, as previously reported (26).…”

Section: Preparation Of Single-cell Suspensions From Tumor and Spleenmentioning

confidence: 99%

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Treatment-Enhanced CD4+Foxp3+ Glucocorticoid-Induced TNF Receptor Family RelatedHigh Regulatory Tumor-Infiltrating T Cells Limit the Effectiveness of Cytokine-Based Immunotherapy

Berhanu¹,

Huang²,

Watkins

et al. 2007

The Journal of Immunology

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Regulatory T cells can suppress activated CD4+ and CD8+ T effector cells and may serve as an impediment to spontaneous or therapeutic type 1 antitumor immunity. In a previous study, we observed minimal therapeutic impact, but significantly enhanced T cell cross-priming and lesional infiltration of tumor-reactive CD8+ T cells into established CMS4 sarcomas after combined treatment of BALB/c mice with rFLt3 ligand (rFL) and recombinant GM-CSF (rGM-CSF). In this study, we show that this cytokine regimen also results in the profound enhancement of CD4+ tumor-infiltrating lymphocytes (TIL) expressing FoxP3, IL-10, and TGF-β mRNA, with 50 or 90% of CD4+ TIL coexpressing the CD25 and glucocorticoid-induced TNFR family related molecules, respectively. Intracellular staining for Foxp3 protein revealed that combined treatment with rFL plus rGM-CSF results in a significant increase in CD4+Foxp3+ T cells in the spleen of both control and tumor-bearing mice, and that nearly half of CD4+ TIL expressed this marker. In addition, CD4+ TIL cells were of an activated/memory (ICOShighCD62LlowCD45RBlow) phenotype and were capable of suppressing allospecific T cell proliferation and IFN-γ production from (in vivo cross-primed) anti-CMS4 CD8+ T cells in vitro, via a mechanism at least partially dependent on IL-10 and TGF-β. Importantly, in vivo depletion of CD4+ T cells resulted in the ability of previously ineffective, rFL plus rGM-CSF therapy-induced CD8+ T cells to now mediate tumor regression.

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Sunitinib facilitates the activation and recruitment of therapeutic anti‐tumor immunity in concert with specific vaccination

Bose

Taylor

Alber

et al. 2011

Intl Journal of Cancer

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133

128

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The multikinase inhibitor sunitinib malate (SUT) has been reported to reduce levels of myeloid suppressor cells and Treg cells in cancer patients, hypothetically diminishing intrinsic impediments for active immunization against tumor-associated antigens in such individuals. The goal of this study was to identify longitudinal immune molecular and cellular changes associated with tumor regression and disease-free status after the treatment of established day 7 s.c. MO5 (B16.OVA) melanomas with SUT alone (1 mg/day via oral gavage for 7 days), vaccination using ovalbumin (OVA) peptide-pulsed dendritic cell [vaccine (VAC)] alone, or the combination of SUT and VAC (SUT/VAC). We observed superior anti-tumor efficacy for SUT/VAC combination approaches, particularly when SUT was applied at the time of the initial vaccination or the VAC boost. Treatment effectiveness was associated with the acute loss of (and/or failure to recruit) cells bearing myeloid-derived suppressor cells or Treg phenotypes within the tumor microenvironment (TME) and the corollary, prolonged enhancement of Type-1 anti-OVA CD8 1 T cell responses in the tumor-draining lymph node and the TME. Enhanced Type-1 T cell infiltration of tumors was associated with treatment-induced expression of vascular cell adhesion molecule-1 (VCAM-1) and CXCR3 ligand chemokines in vascular/peri-vascular cells within the TME, with SUT/VAC therapy benefits conditionally negated upon adminsitration of CXCR3 or VCAM-1 blocking antibodies. These data support the ability of a short 7 day course of SUT to (re)condition the TME to become more receptive to the recruitment and prolonged therapeutic action of (VAC-induced) anti-tumor Tc1 cells.

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Combinational FLt3 Ligand and Granulocyte Macrophage Colony-Stimulating Factor Treatment Promotes Enhanced Tumor Infiltration by Dendritic Cells and Antitumor CD8+ T-Cell Cross-priming but Is Ineffective as a Therapy

Abstract: Dendritic cells play significant roles in the development and maintenance of antitumor immune responses.

Cited by 27 publications

References 46 publications

Coexpression of Flt3 ligand and GM-CSF genes modulates immune responses induced by HER2/neu DNA vaccine

Coexpression of Flt3 ligand and GM-CSF genes modulates immune responses induced by HER2/neu DNA vaccine

Treatment-Enhanced CD4+Foxp3+ Glucocorticoid-Induced TNF Receptor Family RelatedHigh Regulatory Tumor-Infiltrating T Cells Limit the Effectiveness of Cytokine-Based Immunotherapy

Sunitinib facilitates the activation and recruitment of therapeutic anti‐tumor immunity in concert with specific vaccination

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