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Immune priming usin...
Immune priming using DC- and T cell-targeting gene therapy sensitizes both treated and distant B16 tumors to checkpoint inhibition
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- Wenthe, Jessica (author)
- Uppsala universitet,Klinisk immunologi,Science for Life Laboratory, SciLifeLab
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- Naseri, Sedigheh (author)
- Uppsala universitet,Klinisk immunologi,Science for Life Laboratory, SciLifeLab
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- Hellström, Ann-Charlotte (author)
- Uppsala universitet,Klinisk immunologi,Science for Life Laboratory, SciLifeLab
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- Moreno, Rafael (author)
- IDIBELL Inst Catala Oncol, Barcelona 08908, Spain.
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- Ullenhag, Gustav (author)
- Uppsala universitet,Experimentell och klinisk onkologi,Science for Life Laboratory, SciLifeLab,Uppsala Univ Hosp, Dept Oncol, S-75185 Uppsala, Sweden.
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- Alemany, Ramon (author)
- IDIBELL Inst Catala Oncol, Barcelona 08908, Spain.
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- Lövgren, Tanja (author)
- Uppsala universitet,Institutionen för medicinska vetenskaper,Klinisk immunologi
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- Eriksson, Emma (author)
- Uppsala universitet,Klinisk immunologi,Science for Life Laboratory, SciLifeLab,Lokon Pharma AB, S-75320 Uppsala, Sweden.
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- Loskog, Angelica S., 1973- (author)
- Uppsala universitet,Klinisk immunologi,Science for Life Laboratory, SciLifeLab,Lokon Pharma AB, S-75320 Uppsala, Sweden.
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(creator_code:org_t)
- Elsevier, 2022
- 2022
- English.
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In: MOLECULAR THERAPY-ONCOLYTICS. - : Elsevier. - 2372-7705. ; 24, s. 429-442
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Abstract
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- Immune checkpoint inhibitors have revolutionized the treatment of metastatic melanoma, but most tumors show resistance. Resistance is connected to a non-T cell inflamed phenotype partially caused by a lack of functional dendritic cells (DCs) that are crucial for T cell priming. Herein, we investigated whether the adenoviral gene vehicle mLOAd703 carrying both DC- and T cell-activating genes can lead to inflammation in a B16-CD46 model and thereby overcome resistance to checkpoint inhibition therapy. B16-CD46 cells were injected subcutaneously in one or both flanks of immuno-competent C57BL/6J mice. mLOAd703 treatments were given intratumorally alone or in combination with intraperitoneal checkpoint inhibition therapy (anti-PD-1, anti-PD-L1, or anti-TIM-3). Tumor, lymph node, spleen, and serum samples were analyzed for the presence of immune cells and cytokines/chemokines. B16-CD46 tumors were non-inflamed and resistant to checkpoint blockade. In contrast, mLOAd703 treatment led to infiltration of the tumor by CD8(+) T cells, natural killer (NK) cells, and CD103(+) DCs, accompanied by a systemic increase of pro-inflammatory cytokines interferon gamma (IFN-gamma), tumor necrosis factor alpha (TNF-alpha), and interleukin-27 (IL-27). This response was even more pronounced after combining the virus with checkpoint therapy, in particular with anti-PD-L1 and anti-TIM-3, leading to further reduced tumor growth in injected lesions. Moreover, anti-PD-L1 combination also facilitated abscopal responses in non-injected lesions.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Immunologi inom det medicinska området (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Immunology in the medical area (hsv//eng)
Publication and Content Type
- ref (subject category)
- art (subject category)
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