Recently, the latest research result of the team led by Associate Professor Xuanming YANG from the School of Life Sciences and Biotechnology, titled “USP22 deficiency in melanoma mediates resistance to T cells through IFNγ-JAK1-STAT1 signal axis”, was published online on Molecular Therapy, an international renowned journal. The research group found that USP22 can directly deubiquitinate STAT1, and then regulate the resistance to T cells killing through IFNγ-JAK1-STAT1 signaling pathway. The research provides a new target for overcoming the non-response of tumor immunotherapy as well as a new mechanism for tumor escape. Prof. YANG is the corresponding author; doctoral student Min Li and research assistant Yanqin Xu from SJTU are the co-first authors.

The immune checkpoint blockade immunotherapy is an effective treatment for clinical patients with metastatic melanoma, but only ~30% of melanoma patients respond to the therapy and ～70% are non-response. It is urgent to explore the tolerance mechanism of immune checkpoint blockade immunotherapy in the treatment of melanoma patients.

The CRISPR-Cas9 mediated loss-of-function screens was used to do a whole genome knockout model in B16-OVA mouse melanomas. And we found the potential resistance genes USP22 by OT-I T cells killing screening both in vivo and in vitro. Further exploration of the mechanism found that USP22 enhanced the stability of STAT1 through deubiquitinating it, and then regulated IFNγ-JAK1-STAT1 signaling pathway. Similarly, USP22 also enhanced STAT1 stability through deubiquitinating it in human melanoma cells.

The study revealed that the new mechanism of USP22 regulating T cell killing resistance. It is not only of great significance in improving the function of USP22, but also provides important theoretical support for new target drugs for combination therapy with immune checkpoint blockade immunotherapy.

This work was funded by the National Key Research and Development Program (2016YFC1303400), the National Natural Science Foundation of China (81901689, 81971467, and 81671643), and SJTU Science and Technology Innovation Special Fund.

Publication link：https://doi.org/10.1016/j.ymthe.2021.02.018