Abstract
The inhibitory effects of cancer on T cell metabolism have been well established, but the metabolic impact of immunotherapy on tumor cells is poorly understood. Here, we developed a CD4+ T cell-based adoptive immunotherapy protocol that was curative for mice with implanted colorectal tumors. By conducting metabolic profiling on tumors, we show that adoptive immunotherapy profoundly altered tumor metabolism, resulting in glutathione depletion and accumulation of reactive oxygen species (ROS) in tumor cells. We further demonstrate that T cell-derived tumor necrosis factor alpha (TNF-α) can synergize with chemotherapy to intensify oxidative stress and tumor cell death in an NADPH (nicotinamide adenine dinucleotide phosphate hydrogen) oxidase-dependent manner. Reduction of oxidative stress, by preventing TNF-α-signaling in tumor cells or scavenging ROS, antagonized the therapeutic effects of adoptive immunotherapy. Conversely, provision of pro-oxidants after chemotherapy can partially recapitulate the antitumor effects of T cell transfer. These findings imply that reinforcing tumor oxidative stress represents an important mechanism underlying the efficacy of adoptive immunotherapy. Using a preclinical model of colorectal tumors treated with CD4+ T cell-based adoptive immunotherapy, Habtetsion et al. show that profound metabolic changes occur in tumors before tumor regression. T cells shape tumor metabolism through TNF-α which can synergize with chemotherapy, to increase tumor cell oxidative stress through an NOX-dependent mechanism.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 228-242.e6 |
| Journal | Cell Metabolism |
| Volume | 28 |
| Issue number | 2 |
| DOIs | |
| State | Published - Aug 7 2018 |
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Keywords
- CD4+ T cell
- NADPH oxidase
- TNF-α
- adoptive immunotherapy
- chemotherapy
- glutathione
- metabolism
- oxidative stress
- reactive oxygen species
- redox
ASJC Scopus subject areas
- Physiology
- Molecular Biology
- Cell Biology
Cite this
Alteration of Tumor Metabolism by CD4+ T Cells Leads to TNF-α-Dependent Intensification of Oxidative Stress and Tumor Cell Death. / Habtetsion, Tsadik; Ding, Zhi-Chun; Pi, Wenhu; Li, Tao; Lu, Chunwan; Chen, Tingting; Xi, Caixia; Spartz, Helena; Liu, Kebin; Hao, Zhonglin; Mivechi, Nahid F; Huo, Yuqing; Blazar, Bruce R.; Munn, David H; Zhou, Gang.
In: Cell Metabolism, Vol. 28, No. 2, 07.08.2018, p. 228-242.e6.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Alteration of Tumor Metabolism by CD4+ T Cells Leads to TNF-α-Dependent Intensification of Oxidative Stress and Tumor Cell Death
AU - Habtetsion, Tsadik
AU - Ding, Zhi-Chun
AU - Pi, Wenhu
AU - Li, Tao
AU - Lu, Chunwan
AU - Chen, Tingting
AU - Xi, Caixia
AU - Spartz, Helena
AU - Liu, Kebin
AU - Hao, Zhonglin
AU - Mivechi, Nahid F
AU - Huo, Yuqing
AU - Blazar, Bruce R.
AU - Munn, David H
AU - Zhou, Gang
PY - 2018/8/7
Y1 - 2018/8/7
N2 - The inhibitory effects of cancer on T cell metabolism have been well established, but the metabolic impact of immunotherapy on tumor cells is poorly understood. Here, we developed a CD4+ T cell-based adoptive immunotherapy protocol that was curative for mice with implanted colorectal tumors. By conducting metabolic profiling on tumors, we show that adoptive immunotherapy profoundly altered tumor metabolism, resulting in glutathione depletion and accumulation of reactive oxygen species (ROS) in tumor cells. We further demonstrate that T cell-derived tumor necrosis factor alpha (TNF-α) can synergize with chemotherapy to intensify oxidative stress and tumor cell death in an NADPH (nicotinamide adenine dinucleotide phosphate hydrogen) oxidase-dependent manner. Reduction of oxidative stress, by preventing TNF-α-signaling in tumor cells or scavenging ROS, antagonized the therapeutic effects of adoptive immunotherapy. Conversely, provision of pro-oxidants after chemotherapy can partially recapitulate the antitumor effects of T cell transfer. These findings imply that reinforcing tumor oxidative stress represents an important mechanism underlying the efficacy of adoptive immunotherapy. Using a preclinical model of colorectal tumors treated with CD4+ T cell-based adoptive immunotherapy, Habtetsion et al. show that profound metabolic changes occur in tumors before tumor regression. T cells shape tumor metabolism through TNF-α which can synergize with chemotherapy, to increase tumor cell oxidative stress through an NOX-dependent mechanism.
AB - The inhibitory effects of cancer on T cell metabolism have been well established, but the metabolic impact of immunotherapy on tumor cells is poorly understood. Here, we developed a CD4+ T cell-based adoptive immunotherapy protocol that was curative for mice with implanted colorectal tumors. By conducting metabolic profiling on tumors, we show that adoptive immunotherapy profoundly altered tumor metabolism, resulting in glutathione depletion and accumulation of reactive oxygen species (ROS) in tumor cells. We further demonstrate that T cell-derived tumor necrosis factor alpha (TNF-α) can synergize with chemotherapy to intensify oxidative stress and tumor cell death in an NADPH (nicotinamide adenine dinucleotide phosphate hydrogen) oxidase-dependent manner. Reduction of oxidative stress, by preventing TNF-α-signaling in tumor cells or scavenging ROS, antagonized the therapeutic effects of adoptive immunotherapy. Conversely, provision of pro-oxidants after chemotherapy can partially recapitulate the antitumor effects of T cell transfer. These findings imply that reinforcing tumor oxidative stress represents an important mechanism underlying the efficacy of adoptive immunotherapy. Using a preclinical model of colorectal tumors treated with CD4+ T cell-based adoptive immunotherapy, Habtetsion et al. show that profound metabolic changes occur in tumors before tumor regression. T cells shape tumor metabolism through TNF-α which can synergize with chemotherapy, to increase tumor cell oxidative stress through an NOX-dependent mechanism.
KW - CD4+ T cell
KW - NADPH oxidase
KW - TNF-α
KW - adoptive immunotherapy
KW - chemotherapy
KW - glutathione
KW - metabolism
KW - oxidative stress
KW - reactive oxygen species
KW - redox
UR - http://www.scopus.com/inward/record.url?scp=85047723724&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85047723724&partnerID=8YFLogxK
U2 - 10.1016/j.cmet.2018.05.012
DO - 10.1016/j.cmet.2018.05.012
M3 - Article
C2 - 29887396
AN - SCOPUS:85047723724
VL - 28
SP - 228-242.e6
JO - Cell Metabolism
JF - Cell Metabolism
SN - 1550-4131
IS - 2
ER -