T cell therapies have achieved great success in treating hematologic malignancies but facing difficulties in treating solid tumor. Chenqi Xu was invited by Cancer Cell to contribute a preview discussing a CRISPR-based platform for developing T cell therapies, which allows discovery of constructs promoting T cell anti-tumor activity.
In a recent Cell paper by Marson and colleagues, the researchers developed a method for pooled knockin screening of large DNA sequences at the endogenous TCRa constant (TRAC) locus. They designed a 36-member library of barcoded templates, which enables the quantification of on-target integration of each construct. They further developed pooled knockin sequencing (PoKI-seq), combing single-cell transcriptome analysis and pooled knockin screening to measure cell abundance and cell states ex vivo and in vivo. Using this innovative technology, they found that a novel chimeric TGF-bR2-41BB receptor, which convert suppressive TGFb signaling to stimulatory 41BB signaling, enhanced T cell fitness and thus promoted solid tumor clearance. This pooled knockin platform will accelerate discovery of new constructs for T cell therapies.
PD-1, a well-established drug target for cancer immunotherapy, has been recognized as a driver of T cell exhaustion for long time but this concept is now challenged by a recently published paper at Molecular Cell by Okazaki and colleagues. Chenqi Xu was invited by Molecular Cell to contribute a preview discussing these controversial data and proposing his own model of PD-1 function.
In the paper of Okazaki and colleagues, the authors used human and mouse T cell systems to study how PD-1 signaling impacts transcriptome at the early stage of T cell activation. They find PD-1 primarily affects genes that are induced or suppressed by strong TCR signaling, i.e. cytokine genes but not proliferation and exhaustion genes. This paper points out PD-1’s role at the early stage of T cell activation is controlling effector function but not inducing exhaustion. One needs to notice that PD-1 expression is only transient during normal T cell activation. Therefore, the new paper more reflects the function of transient PD-1 signaling. However, at the contexts of cancer or chronic infection, PD-1 expression is persistently induced by chronic antigen exposure. Persistent PD-1 signaling can work together with key transcription factors to induce and reinforce T cell exhaustion status. In summary, PD-1’s role is different under different scenarios and its contribution to T cell exhaustion needs to be further studied.
Temporarily Free link: https://authors.elsevier.com/a/1agzW3vVUPDe88
The T cell receptor (TCR) is one of the most complicated receptors in mammalian cells. Attracted by the complexity and functional importance of TCR, many groups have been studying TCR structure and triggering for decades using diverse biochemical and biophysical tools. Recently, a review, entitled “structural understanding of T cell receptor triggering”, by the research group led by Dr. Chenqi Xu at Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, is published online at Cellular & Molecular Immunology. The review synthesizes the structural studies and discusses the relevance of the conformational change model in TCR triggering.
T cells play essential roles in the adaptive immune response against pathogens and cancer cells. T cells specifically recognize peptide antigens loaded on the major histocompatibility complex (peptide-MHC, pMHC) upon TCR activation. As an octamer complex, TCR comprises an antigen-binding subunit (TCRαβ) and three CD3 signaling subunits (CD3γε, CD3δε, and CD3ζζ). Engagement of TCRαβ with an antigen pMHC leads to tyrosine phosphorylation of the immunoreceptor tyrosine-based activation motif (ITAM) in CD3 cytoplasmic domains, thus translating extracellular binding kinetics to intracellular signaling events. To explain the triggering mechanism of TCR, several models have been proposed, including but not limited to kinetic segregation, serial engagement, kinetic proofreading, and conformational change. Recently, a signiﬁcant breakthrough was made in the TCR ﬁeld. Dong et al. reported a cryo-electron microscopy (cryo-EM) structure of a human TCR–CD3 complex in its unliganded state at 3.7 Å resolution (Nature. 573 (7775): 546-552, 2019). As expected, the TCR-CD3 complex is assembled with a 1:1:1:1 stoichiometry of TCRαβ/ CD3γε/CD3δε/CD3ζζ. Whether conformational change plays an important role in the transmembrane signal transduction of TCR is thus brought into attention again. In the review, we highlight the conformational changes that occur in the extracellular, transmembrane, and intracellular domains upon TCR triggering. Most results corroborate each other and are useful for revealing the mechanism of TCR triggering. Since lipids play essential roles in regulating TCR structure and function, studying the TCR-CD3 complex in a native membrane environment is warranted in future research. Moreover, T cell-based immunotherapies such as TCR-T and CAR-T can be further developed and applied in the clinic based on a better understanding of TCR triggering.
Prof. Chenqi Xu serves as the corresponding author to design the framework and extensively revise the manuscript. Xinyi Xu and Hua Li, a graduate student and an associate professor in the Xu Lab, serve as co-first authors. The work was supported by grants from NSFC grants, CAS grants (Strategic Priority Research Program; Facility-based Open Research Program; Fountain-Valley Life Sciences Fund of University of Chinese Academy of Sciences Education Foundation), MOST, and the Ten Thousand Talent Program “Leading Talent” of China.
Paper link: https://rdcu.be/b1wik.
Cholesterol metabolism plays important roles in health and disease. Modulating cholesterol metabolism has become an emerging avenue to treat multiple types of cancer. Binlu Huang and Chenqi Xu at SIBCB worked together Bao-Liang Song at Wuhan University to write a review article discussing this fast-developing field that is now published at Nature Metabolism.
Cholesterol is an essential building block of cell membranes and a precursor to bile acids and steroid hormones. Beyond these roles, cholesterol metabolites have a variety of biological functions that are poorly understood thus far. As fast-proliferating cells, cancer cells reprogram cholesterol metabolism to support membrane biogenesis and other functional needs. Higher levels of cholesterol biosynthesis, uptake, esterification and oxidation have been observed with various types of cancer cells, driven by intrinsic and extrinsic factors. Tumor microenvironment is often enriched with oxidized cholesterol species, named oxysterols, that have potent immune modulation functions. Typically, oxysterols suppress immune effector cells and promote immune suppressor cells, thus causing an immune suppressive environment to promote tumor progression. Interfering cholesterol metabolism of cancer cells and immune cells shows promising results in clinical and preclinical studies. In addition to numerous works with cholesterol biosynthesis inhibitors such as statin, drugs targeting the cholesterol esterification enzyme and the key transcriptional factor Liver X receptor have been developed and tested in different cancer models. Combinations with existing anti-cancer therapies have also been proven effectively. New therapeutic opportunities in cancer therefore emerge and might eventually benefit patients in the near future.
Prof. Chenqi Xu serves as the corresponding author to design the framework and extensively revise the manuscript. Prof. Bao-Liang Song wrote the first section, and Dr. Binlu Huang, a postdoctoral fellow in the Xu lab, wrote section 2-4.
Paper link: https://rdcu.be/b1tMd.