Huang Bo’s team Published a Paper on Cancer Cell to Reveal the Mechanism of PD-1 Upregulation of Tumor-Specific T Cells - CAMS&PUMC(Beta version) - Chinese Academy of Medical Sciences,Peking Union Medical College,PUMC,CAMS

Huang Bo’s team Published a Paper on Cancer Cell to Reveal the Mechanism of PD-1 Upregulation of Tumor-Specific T Cells

2018-03-15

On March 12, the Cancer Cell published a paper - “Tumor Repopulating Cells Induce PD-1 Expression in CD8+ T Cells by Transferring Kynurenine and AhR Activation”. Associate Researcher Liu Yuying and PhD. candidate Liang Xiaoyu and Dong Wenqian from the Institute of Basic Medical Sciences are its co-first authors and Professor Huang Bo is its corresponding author.

Tumor immunotherapy is to directly or indirectly kill tumor cells through immune cells and immune molecules so as to control or eliminate tumors. This is considered as the hope for human beings to defeat cancer and the hottest tumor research field currently. It mainly relies on the destruction of activated T-cells to tumor cells, and inhibitory immune molecule (immune checkpoint) PD-1 upregulation in tumor-infiltrating T cells and inhibits the T-cell activation through transferring inhibitory signals. Currently, the therapeutic antibody targeting immune checkpoint PD-1 has achieved an unprecedented success in clinical tumor patients. Nevertheless, PD-1 antibody drugs are expensive and of great side effects. Therefore, to seek micromolecule inhibitors of PD-1 becomes the core direction for the current R&D of tumor immunotherapy drugs, and the difficulty is that mechanisms underlying PD-1 upregulation in tumor-infiltrating T cells remain a mystery.

As an essential amino acid, tryptophan can generate various important active molecules such as 5-hydroxytryptamine and melatonin via metabolism in body, but also can produce kynurenine (Kyn) via indoleamine 2,3-dioxygenase (IDO) catalysis, to directly activate the cytosolic transcription factor - aryl hydrocarbon receptor (AhR). Huang Bo’s team has found in previous researches that, the tumor repopulating cells (TRCs) with high tumorigenicity are infiltrated in tumor and their IDO-Kyn-AhR pathway is very active. The immune factor IFN-γ released by T-cells activates this pathway further and induces TRCs in the state of dormancy (Nat Commun. 2017; 8:15207). Moreover, the team has found that, the antiviral immune factor IFN-β can also activate this pathway and better induces TRCs in the state of dormancy (J Clin Invest. 2018; 128:1057-1073). Co-cultivating the activated T-cells and tumor cells, this team has found that the activated T-cells fail to kill TRCs but rather upregulating the PD-1 expression and facilitating TRCs to regulate T-cells for PD-1 expressions. Through a large number of researches, this team has validated the conclusion above. However, the mechanism is very complex. When the activated T-cells interact with TRCs at tumor location, IFN-γ released by T-cells will facilitate TRCs to greatly upregulate tryptophan transporters and IDO to enable tryptophan into TRCs and metabolized as Kyn. After released from cell by TRCs, Kyn will enter T-cells via the Kyn transporters on T-cell surface to activate the AhR of T-cells. Then AhR will enter nucleus and combine with PD-1 promoter directly to promote the PD-1 expression (see the figure attached). The interpretation of this mechanism not only deepens our understanding of the current tumor immunology theoretically but also contributes to the development of new tumor immunotherapy strategy practically.

 

CD8+ T-cells upregulate PD-1 expression. In the immunological synapse, T-cells release a large number of IFN-γs, which can upregulate the SLC1A5 expression of Trp to increase Trp intake and upregulate the IDO1 expression to accelerate Trp towards Kyn via metabolism on the other hand. In this way, mass Kyns are released from cells and enter T-cells via the Kyn transporters on T-cell surface to activate the AhR of T-cells. Then AhR will enter nucleus and combine with PD-1 promoter directly to promote the PD-1 expression.

This research was conducted by Huang Bo’s team and is sponsored by the CAMS’s Medical and Health Sciences Innovation Initiative (2016-I2M-1-007) and National Natural Science Foundation of China. Professor Cao Xuetao of the Institute of Basic Medical Sciences, Professor Hu Zhuowei of the Institute of Materia Medica, and Professor Qin Xiaofeng of the Suzhou Institute of Systems Medicine are the investigators of the research.

 

(Institute of Basic Medical Sciences)