The international academic journal PNAS published online the latest research of Lou Jizhong's research group from the Institute of Biophysics, Xu Chenqi's research group from the Center for Excellence in Molecular Cell Science, and Chen Wei's research group from Zhejiang University School of Medicine, "Self-programmed dynamics of T cell receptor condensation". This work found that the T cell receptor (TCR) regulates T cell activation through a self-programmed aggregation and depolymerization mechanism based on CD3ε/Lck, which explained the sensitivity and rapidity of the TCR signaling pathway from the perspective of phase separation and further enriched the Csk-based negative regulation mechanism of TCR.

Dr. Chen Hui from the Institute of Biophysics, Xu Xinyi, a doctoral student at the Center for Excellence in Molecular and Cell Science, and Dr. Hu Wei, a distinguished researcher at the Nephrology Center of the First Affiliated Hospital of Zhejiang University School of Medicine, are the co-first authors of this article. Professor Lou Jizhong, Xu Chenqi, and Chen Wei are the co-corresponding authors. Director Lou Changjie of Harbin Medical University Cancer Hospital, Professor Liu Wanli of Tsinghua University, and Professor Jiang Ning of the University of Pennsylvania also made important contributions to this study. The research work was funded by the Natural Science Foundation of China, the Strategic Pioneering Technology Project of the Chinese Academy of Sciences (Category B), and the National Key Research and Development Project.

Recently, Cancer Cell published the research from Dr. Chenqi Xu’s group at Hangzhou Institute for Advanced Study and CAS Center for Excellence in Molecular Cell Science and Dr. Bao-Liang Song’s group at Wuhan University entitled “Exhaustion-associated cholesterol deficiency dampens the cytotoxic arm of antitumor immunity”. This study revealed a new mechanism of TME inducing T-cell dysfunction through cholesterol metabolism. Oxysterols in TME cause cholesterol deficiency of intratumoral T cells, subsequently leading to aberrant metabolic and signaling pathways that drive T cell exhaustion/dysfunction.

The concept of targeting cholesterol metabolism to treat cancer has been widely tested in clinics but the benefits are modest, calling for a complete understanding of cholesterol metabolism of intratumoral cells. The authors firstly characterized the cholesterol atlas of the TME and found that TILs had cholesterol deficiency while immunosuppressive myeloid cells and tumor cells had cholesterol abundance and consume most of the environmental cholesterol. Then the authors found that low cholesterol levels inhibited T-cell proliferation and caused autophagy-mediated apoptosis, particularly for cytotoxic T cells. The authors further revealed that oxysterols enriched in the TME mediated reciprocal alterations of the LXR and SREBP2 pathways to cause cholesterol deficiency of T cells, subsequently leading to aberrant metabolic and signaling pathways that drive T cell exhaustion/dysfunction. The authors developed a new cholesterol-modulation strategy to improve the performance of CAR-T cells. LXRb depletion in CAR-T cells led to improved antitumor function against solid tumor. Since T-cell cholesterol metabolism and oxysterols are generally linked to other diseases, the new mechanism and cholesterol-normalization strategy might have potential applications elsewhere.

Postdoc Chengsong Yan from Hangzhou Institute for Advanced Study and CAS Center for Excellence in Molecular Cell Science, Ph.D. candidates Lin Zheng, Shutan Jiang, Haochen Yang and Postdoc Jun Guo from CAS Center for Excellence in Molecular Cell Science are the co-first authors. Dr. Chenqi Xu and Dr. Bao-Liang Song are the co-corresponding authors.

The international academic journal PNAS published online the latest research of Lou Jizhong's research group from the Institute of Biophysics, Xu Chenqi's research group from the Center for Excellence in Molecular Cell Science, and Chen Wei's research group from Zhejiang University School of Medicine, "Self-programmed dynamics of T cell receptor condensation". This work found that the T cell receptor (TCR) regulates T cell activation through a self-programmed aggregation and depolymerization mechanism based on CD3ε/Lck, which explained the sensitivity and rapidity of the TCR signaling pathway from the perspective of phase separation and further enriched the Csk-based negative regulation mechanism of TCR.

Dr. Chen Hui from the Institute of Biophysics, Xu Xinyi, a doctoral student at the Center for Excellence in Molecular and Cell Science, and Dr. Hu Wei, a distinguished researcher at the Nephrology Center of the First Affiliated Hospital of Zhejiang University School of Medicine, are the co-first authors of this article. Professor Lou Jizhong, Xu Chenqi, and Chen Wei are the co-corresponding authors. Director Lou Changjie of Harbin Medical University Cancer Hospital, Professor Liu Wanli of Tsinghua University, and Professor Jiang Ning of the University of Pennsylvania also made important contributions to this study. The research work was funded by the Natural Science Foundation of China, the Strategic Pioneering Technology Project of the Chinese Academy of Sciences (Category B), and the National Key Research and Development Project.

CAR T-cell therapy is a type of adoptive cell therapy to treat cancer. Using genetic engineering, T cells from patients are equipped with chimeric antigen receptor (CAR) to specifically recognize tumor antigen and kill tumor cells. However, CAR-T cell therapy is facing major clinical challenges including cytokine release syndrome and poor persistence. Therefore, it is important to design CAR-T cells with high persistence, little side effects and strong anti-tumor activity.

Recently, Dr. Chenqi Xu’s group at CAS Center for Excellence in Molecular Cell Science, Dr. Catherine Chiulan Wong’s group at Peking University and Dr. Enfu Hui’s group at University California, San Diego developed a new strategy of CAR-T cell therapy, which has reduced cytokine production, enhanced cell persistence and better anti-tumor function than clinical used 28Z CAR-T cells. This study was published in Cell entitled “Multiple Signaling Roles of CD3ε and Its Application in CAR-T Cell Therapy” on July 29.

T cell receptor (TCR) mediates antigen-induced signaling through its associated CD3ε, δ, γ, and ζ. Using quantitative mass spectrometry, the authors simultaneously quantitated the phosphorylation of the immunoreceptor tyrosine-based activation motif (ITAM) of all CD3 chains upon TCR stimulation. The results showed that CD3ε ITAMs was mono-phosphorylated, owing to Lck kinase selectivity, and specifically recruited the inhibitory Csk kinase to attenuate TCR signaling, suggesting that TCR is a self-restrained signaling machinery containing both activating and inhibitory motifs. Next, the authors incorporated CD3ε cytoplasmic domain into the clinical used 28Z CAR, and found that the new E28Z CAR-T cells had improved antitumor activity. Mechanistically, the Csk-recruiting ITAM of CD3ε reduced CAR-T cell cytokine production whereas the basic residue rich sequence (BRS) of CD3ε promoted CAR-T cell persistence via p85 recruitment. Considering the strong anti-tumor activity of E28Z CAR-T cells in both blood tumor and solid tumor models, these results provide a solid rationale to explore its promising translational potentials in treating blood and solid malignancies.

Ph.D. candidates Wei Wu, Qiuping Zhou and Xiaoshan Shi from CAS Center for Excellence in Molecular Cell Science and Dr. Takeya Masubuchi from University California, San Diego are the co-first authors. Dr. Chenqi Xu, Dr. Catherine Chiulan Wong and Dr. Enfu Hui are the co-corresponding authors. Dr. Haopeng Wang from ShanghaiTech University and Dr. Jie Sun from Zhejiang University participate the study. Dr. Chenqi Xu is the adjunct researcher of Hangzhou Institute For Advanced Study of the Chinese Academy of Sciences.

Clinical used 28Z CAR-T cells are facing major clinical challenges including cytokine release syndrome and poor persistence. E28Z CAR-T cells incorporating the CD3ε cytoplasmic domain have reduced cytokine production due to Csk-recruiting ITAM of CD3εand enhanced persistence through p85- recruiting BRS of CD3ε.