Abstract
Increasing evidence demonstrates that interleukin-10 (IL-10), known as an immunosuppressive cytokine, induces antitumor effects depending on CD8+ T cells. However, it remains elusive how immunosuppressive effects of IL-10 contribute to CD8+ T cell-mediated antitumor immunity. We generated Cetuximab-based IL-10 fusion protein (CmAb-(IL10)2) to prolong its half-life and allow tumor-targeted delivery of IL-10. Our results demonstrated potent antitumor effects of CmAb-(IL10)2 with reduced toxicity. Moreover, we revealed a mechanism of CmAb-(IL10)2 preventing dendritic cell (DC)-mediated CD8+ tumor-infiltrating lymphocyte apoptosis through regulating IFN-γ production. When combined with immune checkpoint blockade, CmAb-(IL10)2 significantly improves antitumor effects in mice with advanced tumors. Our findings reveal a DC-regulating role of IL-10 to potentiate CD8+ T cell-mediated antitumor immunity and provide a potential strategy to improve cancer immunotherapy. Qiao et al. generate a Cetuximab-based IL-10 fusion protein for EGFR-targeted delivery of IL-10 to tumors, in which IL-10 regulates IFN-γ production by dendritic cells and enhances CD8+ T cell-dependent antitumor responses. The fusion protein shows high efficacy alone and in combination with anti-PD-L1/CTLA-4.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 901-915.e4 |
| Journal | Cancer Cell |
| Volume | 35 |
| Issue number | 6 |
| DOIs | |
| State | Published - Jun 10 2019 |
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Keywords
- apoptosis
- IL-10
- immunotherapy
- TILs
- toxicity
- tumor targeting
ASJC Scopus subject areas
- Oncology
- Cell Biology
- Cancer Research
Cite this
Targeting Tumors with IL-10 Prevents Dendritic Cell-Mediated CD8+ T Cell Apoptosis. / Qiao, Jian; Liu, Zhida; Dong, Chunbo; Luan, Yan; Zhang, Anli; Moore, Casey; Fu, Kai; Peng, Jianjian; Wang, Yang; Ren, Zhenhua; Han, Chuanhui; Xu, Ting; Fu, Yang-Xin.
In: Cancer Cell, Vol. 35, No. 6, 10.06.2019, p. 901-915.e4.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Targeting Tumors with IL-10 Prevents Dendritic Cell-Mediated CD8+ T Cell Apoptosis
AU - Qiao, Jian
AU - Liu, Zhida
AU - Dong, Chunbo
AU - Luan, Yan
AU - Zhang, Anli
AU - Moore, Casey
AU - Fu, Kai
AU - Peng, Jianjian
AU - Wang, Yang
AU - Ren, Zhenhua
AU - Han, Chuanhui
AU - Xu, Ting
AU - Fu, Yang-Xin
PY - 2019/6/10
Y1 - 2019/6/10
N2 - Increasing evidence demonstrates that interleukin-10 (IL-10), known as an immunosuppressive cytokine, induces antitumor effects depending on CD8+ T cells. However, it remains elusive how immunosuppressive effects of IL-10 contribute to CD8+ T cell-mediated antitumor immunity. We generated Cetuximab-based IL-10 fusion protein (CmAb-(IL10)2) to prolong its half-life and allow tumor-targeted delivery of IL-10. Our results demonstrated potent antitumor effects of CmAb-(IL10)2 with reduced toxicity. Moreover, we revealed a mechanism of CmAb-(IL10)2 preventing dendritic cell (DC)-mediated CD8+ tumor-infiltrating lymphocyte apoptosis through regulating IFN-γ production. When combined with immune checkpoint blockade, CmAb-(IL10)2 significantly improves antitumor effects in mice with advanced tumors. Our findings reveal a DC-regulating role of IL-10 to potentiate CD8+ T cell-mediated antitumor immunity and provide a potential strategy to improve cancer immunotherapy. Qiao et al. generate a Cetuximab-based IL-10 fusion protein for EGFR-targeted delivery of IL-10 to tumors, in which IL-10 regulates IFN-γ production by dendritic cells and enhances CD8+ T cell-dependent antitumor responses. The fusion protein shows high efficacy alone and in combination with anti-PD-L1/CTLA-4.
AB - Increasing evidence demonstrates that interleukin-10 (IL-10), known as an immunosuppressive cytokine, induces antitumor effects depending on CD8+ T cells. However, it remains elusive how immunosuppressive effects of IL-10 contribute to CD8+ T cell-mediated antitumor immunity. We generated Cetuximab-based IL-10 fusion protein (CmAb-(IL10)2) to prolong its half-life and allow tumor-targeted delivery of IL-10. Our results demonstrated potent antitumor effects of CmAb-(IL10)2 with reduced toxicity. Moreover, we revealed a mechanism of CmAb-(IL10)2 preventing dendritic cell (DC)-mediated CD8+ tumor-infiltrating lymphocyte apoptosis through regulating IFN-γ production. When combined with immune checkpoint blockade, CmAb-(IL10)2 significantly improves antitumor effects in mice with advanced tumors. Our findings reveal a DC-regulating role of IL-10 to potentiate CD8+ T cell-mediated antitumor immunity and provide a potential strategy to improve cancer immunotherapy. Qiao et al. generate a Cetuximab-based IL-10 fusion protein for EGFR-targeted delivery of IL-10 to tumors, in which IL-10 regulates IFN-γ production by dendritic cells and enhances CD8+ T cell-dependent antitumor responses. The fusion protein shows high efficacy alone and in combination with anti-PD-L1/CTLA-4.
KW - apoptosis
KW - IL-10
KW - immunotherapy
KW - TILs
KW - toxicity
KW - tumor targeting
UR - http://www.scopus.com/inward/record.url?scp=85066144973&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85066144973&partnerID=8YFLogxK
U2 - 10.1016/j.ccell.2019.05.005
DO - 10.1016/j.ccell.2019.05.005
M3 - Article
C2 - 31185213
AN - SCOPUS:85066144973
VL - 35
SP - 901-915.e4
JO - Cancer Cell
JF - Cancer Cell
SN - 1535-6108
IS - 6
ER -