Necroptotic‐susceptible dendritic cells exhibit enhanced antitumor activities in mice
Abstract Introduction Priming of tumor‐specific T cells is a key to antitumor immune response and inflammation, in turn, is crucial for proper T‐cell activation. As antigen‐presenting cells can activate T cells, dendritic cells (DCs) loaded with tumor antigens have been used as immunotherapeutics ag...
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doaj-e4b59616a6b848acbc338b684affcd3a2020-11-25T02:44:18ZengWileyImmunity, Inflammation and Disease2050-45272020-09-018346847910.1002/iid3.330Necroptotic‐susceptible dendritic cells exhibit enhanced antitumor activities in miceZhanran Zhao0Guangzhi Zhang1Yuefang Sun2Astar Winoto3Department of Molecular and Cell Biology, Cancer Research Laboratory University of California Berkeley CaliforniaDepartment of Molecular and Cell Biology, Cancer Research Laboratory University of California Berkeley CaliforniaDepartment of Molecular and Cell Biology, Cancer Research Laboratory University of California Berkeley CaliforniaDepartment of Molecular and Cell Biology, Cancer Research Laboratory University of California Berkeley CaliforniaAbstract Introduction Priming of tumor‐specific T cells is a key to antitumor immune response and inflammation, in turn, is crucial for proper T‐cell activation. As antigen‐presenting cells can activate T cells, dendritic cells (DCs) loaded with tumor antigens have been used as immunotherapeutics against certain cancer in humans but their efficacy is modest. Necroptosis is a form of programmed cell death that results in the release of inflammatory contents. We previously generated mice with DC deficiency in a negative regulator of necroptosis, Fas‐associated death domain (FADD), and found that these mice suffer from systemic inflammation due to necroptotic DCs. We hypothesize that FADD‐deficient DCs could serve as a better vaccine than wild‐type (WT) DCs against tumors. Materials and Methods FADD‐deficient and WT mouse DCs loaded with the relevant tumor peptide were injected onto mice before or after the syngeneic tumor challenge. DC vaccinations were repeated two more times and anti‐PD‐1 antibodies were coinjected in some experiments. Tumor sizes were measured by caliper, and the percentages of tumor‐free mice or mice survived were examined over time. The cytometric analysis was carried out to analyze various immune populations. Results In two separate tumor models, we find that mice receiving FADD‐deficient DCs as vaccine rejected tumors significantly better than those receiving a WT DC vaccine. Tumor growth was severely hampered, and survival extended in these mice. More activated CD8 T cells together with elevated cytokines were observed in mice receiving the FADD‐deficient DC vaccine. Furthermore, we observed these effects were potent enough to protect against tumor challenge postinjection and can work in conjunction with anti‐PD‐1 antibodies to reduce the tumor growth. Conclusions Necroptotic‐susceptible DCs are better antitumor vaccines than WT DCs in mice. Our findings suggest that necroptosis‐driven inflammation by DCs may be a novel avenue to generating a strong adaptive antitumor response in the clinical setting.https://doi.org/10.1002/iid3.330dendritic cellsFADDnecroptosisPD‐1 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Zhanran Zhao Guangzhi Zhang Yuefang Sun Astar Winoto |
spellingShingle |
Zhanran Zhao Guangzhi Zhang Yuefang Sun Astar Winoto Necroptotic‐susceptible dendritic cells exhibit enhanced antitumor activities in mice Immunity, Inflammation and Disease dendritic cells FADD necroptosis PD‐1 |
author_facet |
Zhanran Zhao Guangzhi Zhang Yuefang Sun Astar Winoto |
author_sort |
Zhanran Zhao |
title |
Necroptotic‐susceptible dendritic cells exhibit enhanced antitumor activities in mice |
title_short |
Necroptotic‐susceptible dendritic cells exhibit enhanced antitumor activities in mice |
title_full |
Necroptotic‐susceptible dendritic cells exhibit enhanced antitumor activities in mice |
title_fullStr |
Necroptotic‐susceptible dendritic cells exhibit enhanced antitumor activities in mice |
title_full_unstemmed |
Necroptotic‐susceptible dendritic cells exhibit enhanced antitumor activities in mice |
title_sort |
necroptotic‐susceptible dendritic cells exhibit enhanced antitumor activities in mice |
publisher |
Wiley |
series |
Immunity, Inflammation and Disease |
issn |
2050-4527 |
publishDate |
2020-09-01 |
description |
Abstract Introduction Priming of tumor‐specific T cells is a key to antitumor immune response and inflammation, in turn, is crucial for proper T‐cell activation. As antigen‐presenting cells can activate T cells, dendritic cells (DCs) loaded with tumor antigens have been used as immunotherapeutics against certain cancer in humans but their efficacy is modest. Necroptosis is a form of programmed cell death that results in the release of inflammatory contents. We previously generated mice with DC deficiency in a negative regulator of necroptosis, Fas‐associated death domain (FADD), and found that these mice suffer from systemic inflammation due to necroptotic DCs. We hypothesize that FADD‐deficient DCs could serve as a better vaccine than wild‐type (WT) DCs against tumors. Materials and Methods FADD‐deficient and WT mouse DCs loaded with the relevant tumor peptide were injected onto mice before or after the syngeneic tumor challenge. DC vaccinations were repeated two more times and anti‐PD‐1 antibodies were coinjected in some experiments. Tumor sizes were measured by caliper, and the percentages of tumor‐free mice or mice survived were examined over time. The cytometric analysis was carried out to analyze various immune populations. Results In two separate tumor models, we find that mice receiving FADD‐deficient DCs as vaccine rejected tumors significantly better than those receiving a WT DC vaccine. Tumor growth was severely hampered, and survival extended in these mice. More activated CD8 T cells together with elevated cytokines were observed in mice receiving the FADD‐deficient DC vaccine. Furthermore, we observed these effects were potent enough to protect against tumor challenge postinjection and can work in conjunction with anti‐PD‐1 antibodies to reduce the tumor growth. Conclusions Necroptotic‐susceptible DCs are better antitumor vaccines than WT DCs in mice. Our findings suggest that necroptosis‐driven inflammation by DCs may be a novel avenue to generating a strong adaptive antitumor response in the clinical setting. |
topic |
dendritic cells FADD necroptosis PD‐1 |
url |
https://doi.org/10.1002/iid3.330 |
work_keys_str_mv |
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