The latest revelation on the mechanism of tumor specific T cells upregulating PD-1 by Bo Huang’s Team
Source：Bo Huang
2018-03-28
On March 12th, Professor Bo Huang’s group from the Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, published a paper in Cancer Cell titled "Tumor repopulating cells induce PD-1 expression in CD8+ T cells by transferring kynurenine and AhR activation."
Cancer immunotherapy aims to control or eliminate tumors using immune cells and immune molecules, with the potential to overcome cancer and is currently the hottest field in cancer research. Tumor immunotherapy relies on the killing of tumor cells by activated T cells. Inhibitory immune molecules, such as PD-1, show up-regulated expression on the surface of T cells in tumor tissues and prevent T cell activation by transmitting inhibitory signals. Therefore, inhibiting the PD-1 signal is like removing the foot on the brake and allowing the car (T cell) to move again. The current therapeutic antibody against the immunological checkpoint, PD-1, has achieved unprecedented success in cancer patients. However, PD-1 antibody drugs are expensive and have numerous side effects. Therefore, finding small molecular blockers of PD-1 has become the primary direction of current tumor immunotherapy drug development, but the difficulty is that the mechanism by which T cells up-regulate the expression of PD-1 molecules in tumor tissues has been a mystery.
Tryptophan, an essential amino acid, not only metabolizes important reactive molecules, such as serotonin and melatonin in the body, but also catalyzes the production of kynuric acid (Kyn) via indoleamine 2,3-dioxygenase (IDO) to directly activate the cytosolic transcription factor aromatic hydrocarbon receptor (AhR). The previous study of Huang Bo's research team found that the IDO-Kyn-AhR pathway is highly active in the tumor-producing cells (Tumor repopulating cells, TRCs) of tumor tissues, and is further enhanced by the immune factor IFN-γ released by T cells. Activation of this pathway induced TRC dormancy (Nat Commun. 2017;8:15207); and in addition the team also found that the antiviral immune factor IFN-β also activates this pathway and induces TRC dormancy more effectively (J Clin Invest. 2018;128:1057-1073). Since T cells use IDO-Kyn-AhR to attack TRCs, do TRCs also use this metabolic pathway to counter T cells? When activated T cells were co-cultured with tumor cells, research showed that activated T cells not only can’t kill TRCs, but T cells displayed an enhanced upregulation of PD-1 expression, suggesting that TRCs regulate PD-1 expression on T cells. After further investigation, the team confirmed this conclusion, but its mechanism remains very complicated. When activated T cells interact with TRCs at the tumor site, IFN-γ released by T cells strongly induces expression of the Tryptophan transporter and IDO in TRCs, allowing large amounts of tryptophan to enter TRCs and be metabolized to Kyn; Kyn is then released by TRCs. Subsequently, Kyn is taken up by Kyn transporters on T cell surface, enters the T cell and activates AhR in the T cell. AhR directly shift into the nucleus, binding the PD-1 promoter, and thus stimulates PD-1 expression (see photos). The interpretation of this mechanism not only deepens our understanding of tumor immunity in theory, but also helps us to develop new tumor immunotherapy strategies.
In immune synapses, T cells release a large amount of IFN-γ. Extracellular IFN-γ upregulates the Trp transporter-SLC1A5 expression on tumor cells and increases Trp uptake. Moreover, IFN-γ upregulates IDO1 expression and accelerates Trp metabolism to Kyn. Thus, a large amount of Kyn is released outside the cell, enters T cells intracellularly through the T cell-expressed Kyn transporter, activates AhR of T cells, allowing AhR to enter the nucleus and binds to the PD-1 promoter, ultimately stimulating PD-1 expression.
The study was funded by the Chinese Academy of Medical Sciences (2016-I2M-1-007) and the National Natural Science Foundation. Associate Research Fellow Yuying Liu, and two Ph.D. students Xiaoyu Liang and Wenqian Dong, are the co-authors of this article. Prof. Xuetao Cao of the Institute of Basic Medicine, Prof. Zhuowei Hu of the Institute of Pharmaceutical Research, and Prof. Xiaofeng Qin of the Suzhou Institute of System Medicine participated in the study.
Cancer immunotherapy aims to control or eliminate tumors using immune cells and immune molecules, with the potential to overcome cancer and is currently the hottest field in cancer research. Tumor immunotherapy relies on the killing of tumor cells by activated T cells. Inhibitory immune molecules, such as PD-1, show up-regulated expression on the surface of T cells in tumor tissues and prevent T cell activation by transmitting inhibitory signals. Therefore, inhibiting the PD-1 signal is like removing the foot on the brake and allowing the car (T cell) to move again. The current therapeutic antibody against the immunological checkpoint, PD-1, has achieved unprecedented success in cancer patients. However, PD-1 antibody drugs are expensive and have numerous side effects. Therefore, finding small molecular blockers of PD-1 has become the primary direction of current tumor immunotherapy drug development, but the difficulty is that the mechanism by which T cells up-regulate the expression of PD-1 molecules in tumor tissues has been a mystery.
Tryptophan, an essential amino acid, not only metabolizes important reactive molecules, such as serotonin and melatonin in the body, but also catalyzes the production of kynuric acid (Kyn) via indoleamine 2,3-dioxygenase (IDO) to directly activate the cytosolic transcription factor aromatic hydrocarbon receptor (AhR). The previous study of Huang Bo's research team found that the IDO-Kyn-AhR pathway is highly active in the tumor-producing cells (Tumor repopulating cells, TRCs) of tumor tissues, and is further enhanced by the immune factor IFN-γ released by T cells. Activation of this pathway induced TRC dormancy (Nat Commun. 2017;8:15207); and in addition the team also found that the antiviral immune factor IFN-β also activates this pathway and induces TRC dormancy more effectively (J Clin Invest. 2018;128:1057-1073). Since T cells use IDO-Kyn-AhR to attack TRCs, do TRCs also use this metabolic pathway to counter T cells? When activated T cells were co-cultured with tumor cells, research showed that activated T cells not only can’t kill TRCs, but T cells displayed an enhanced upregulation of PD-1 expression, suggesting that TRCs regulate PD-1 expression on T cells. After further investigation, the team confirmed this conclusion, but its mechanism remains very complicated. When activated T cells interact with TRCs at the tumor site, IFN-γ released by T cells strongly induces expression of the Tryptophan transporter and IDO in TRCs, allowing large amounts of tryptophan to enter TRCs and be metabolized to Kyn; Kyn is then released by TRCs. Subsequently, Kyn is taken up by Kyn transporters on T cell surface, enters the T cell and activates AhR in the T cell. AhR directly shift into the nucleus, binding the PD-1 promoter, and thus stimulates PD-1 expression (see photos). The interpretation of this mechanism not only deepens our understanding of tumor immunity in theory, but also helps us to develop new tumor immunotherapy strategies.
CD8+ T cells up-regulate PD-1 expression
In immune synapses, T cells release a large amount of IFN-γ. Extracellular IFN-γ upregulates the Trp transporter-SLC1A5 expression on tumor cells and increases Trp uptake. Moreover, IFN-γ upregulates IDO1 expression and accelerates Trp metabolism to Kyn. Thus, a large amount of Kyn is released outside the cell, enters T cells intracellularly through the T cell-expressed Kyn transporter, activates AhR of T cells, allowing AhR to enter the nucleus and binds to the PD-1 promoter, ultimately stimulating PD-1 expression.
The study was funded by the Chinese Academy of Medical Sciences (2016-I2M-1-007) and the National Natural Science Foundation. Associate Research Fellow Yuying Liu, and two Ph.D. students Xiaoyu Liang and Wenqian Dong, are the co-authors of this article. Prof. Xuetao Cao of the Institute of Basic Medicine, Prof. Zhuowei Hu of the Institute of Pharmaceutical Research, and Prof. Xiaofeng Qin of the Suzhou Institute of System Medicine participated in the study.
