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Chinese scientists find how PD-1, a key drug target for cancer immunotherapy, is degraded in T cells

 

On November 29, 2018 (Beijing time), Nature publishes online “FBXO38 mediates PD-1 ubiquitination and regulates anti-tumour immunity of T cells” by Prof. Chenqi Xu's research group at Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences. This study reveals a degradation mechanism of immune checkpoint molecule PD-1 and demonstrates the significance of this mechanism in antitumor immunity.

T cells play an important role in monitoring and killing of tumours. However, tumour cells can suppress T-cell function by activating the signalling of immune checkpoint molecules, such as PD-1, expressed on the T-cell surface. In clinic, blocking antibodies against PD-1 or its ligand PD-L1 has been widely used to treat more than 10 types of cancers, such as lung cancer, liver cancer and kidney cancer. Tasuku Honjo, the Japanese immunologist who identified the PD-1 molecule, won the Nobel Prize in Physiology or Medicine in 2018. Despite of the huge clinical success of PD-1 related therapies, there are still many fundamental questions of PD-1 biology remain to be answer, such as the key question why PD-1 is highly upregulated in the tumour microenvironment.

Chenqi Xu’s group has been systematically studying T-cell signalling and metabolism since his return from Harvard Medical School to Chinese Academy of Sciences in 2009. His earlier findings include the discoveries of new regulatory mechanisms of T-cell receptor and CD28 signalling as well as new means of cancer immunotherapy based on modulation of T-cell cholesterol metabolism (Nature 2013, Nature 2016, Nature Structural & Molecular Biology 2017). In this study, his group investigated PD-1 regulation from a new angle. They find that PD-1 protein level can be downregulated via a ubiquitin-mediated proteasome degradation pathway. The key regulatory protein involved in this process is named FBXO38, an E3 ubiquitin ligase whose function has been rarely studied before. FBXO38 can catalyse the addition of a poly-ubiquitination tag on PD-1, and the labelled PD-1 is then sorted to proteasome for degradation. This degradation pathway however is suppressed in the tumour microenvironment. The level of FBXO38 is significantly downregulated in tumour infiltrating T cells, which leads to accumulation of more PD-1 molecules on T cell surface and suppression of T-cell antitumor function. They further show that interleukin-2 (IL-2), a FDA-approved drug against skin and kidney cancers, can rescue FBXO38 level in the tumour microenvironment to reduce PD-1 level and to reinvigorate T-cell activity.

In summary, this study reports a new regulatory mechanism of the important drug target PD-1, helping us better understand the immune response to tumours and design more effective immunotherapy. This research was mainly conducted by Prof. Chenqi Xu’s team. Ph.D students Xiangbo Meng and Xiwei Liu are co-first authors. Several other research teams contribute to this research, including Prof. Wei Yang of Southern Medical University, Prof. Lai Wei and Prof. Penghui Zhou of Sun Yat-sen University, Professor Xiaowu Huang of Zhongshan Hospital, Medical College of Fudan University, Prof. Xiaolong Liu and Prof. Ronggui Hu of Shanghai Institute of Biochemistry and Cell Biology, and Prof. Shao-cong Sun of MD Anderson Cancer Center, USA. Funding sources of this research include the National Natural Science Foundation of China, the Chinese Academy of Sciences, the Shanghai Science Committee and the Ten thousand talent program of the Organization Department of the CPC.