The Zhang laboratory at CIMR works on the identification of key regulatory pathways in tumor immunology and autoimmune diseases, by genome-wide functional screenings in vitro and in vivo, multi-omics analysis of patient samples, and bioinformatic analysis. The lab is developing novel therapeutic strategies for tumor and autoimmune diseases, which will be translated into clinical trials.

The research directions mainly include:

In recent years, immunotherapy is becoming one of most promising strategies to treat tumors. However, the mechanisms that why current immunotherapy only show significant efficacy for certain tumor types and patients are currently unclear. By combining in vitro and in vivo animal models with customized CRISPR/Cas9 functional screenings, as well as multi-omics analysis of patient samples, the lab aims to systematically identify new genes and regulatory pathways that can enhance the efficacy of tumor immunotherapy.

While the adaptive cellular immunity mediated by T lymphocytes plays important roles in tumor immune response, the roles of B lymphocytes in tumor initiation, development, and treatment have only been noticed in recent years. Recent studies demonstrate that B-cells and tertiary lymphoid structures (TLSs) within tumors are associated with a better prognosis for patients receive immunotherapy. The lab is combining multi-omics analysis of human patient samples with mouse tumor models to analyze the roles of B lymphocytes in tumor immunology.

With the in-depth understanding of molecular and cellular mechanisms in human diseases, strategies to target specific pathogenic cells and/or their progenitors have rapidly developed recently. Among them, protein engineering (such as monoclonal antibodies, bi-specific antibodies, antibody-drug-conjugates (ADC)) and cell therapy (such as chimeric antigen receptor T cells (CAR-T), CAR-NK, CAR-Macrophage, etc.) have shown great efficacy on some human tumors. In recent years, similar targeting strategies have been expanded to other human diseases, such as autoimmune diseases, heart fibrosis, and aging-related diseases. The lab is developing new generation therapeutic strategies for human diseases.

Hu QT*, Hong Y*, Qi P*, Lu GQ, Mai XY, Xu S, He XY, Guo Y, Gao LL, Jing ZY, Wang JW, Cai T, Zhang Y^#. Atlas of breast cancer infiltrated B-lymphocytes revealed by paired single-cell RNA-sequencing and antigen receptor profiling. Nature Communications, 2021, 12: 2186. DOI: 10.1038/s41467-021-22300-2

Hua XM*, Hu G*, Hu QT*, Chang Y, Hu YQ, Gao LL, Chen X, Yang PC, Zhang Y^#, Li MY^#, Song JP^#.  Single-Cell RNA Sequencing to Dissect the Immunological Network of Autoimmune Myocarditis. Circulation, 2020, 142: 384-400. DOI: 10.1161/CIRCULATIONAHA.119.043545

Han DQ, Hong Y, Mai XY, Hu QT, Lu GQ, Duan JZ, Xu JR, Si XF, Zhang Y^#. Systematical study of the mechanistic factors regulating genome dynamics in vivo by CRISPRsie. Journal of Molecular Cell Biology, 2019, 11: 1018-1020. DOI: 10.1093/jmcb/mjz074

Duan JZ*, Lu GQ*, Hong Y*, Hu QT*, Mai XY, Guo J, Si XF, Wang FC, Zhang Y^#. Live imaging and tracking of genome regions in CRISPR/dCas9 knock-in mice. Genome Biology, 2018, 19: 192. DOI: 10.1186/s13059-018-1530-1

Hong Y, Lu GQ, Duan JZ, Liu WJ, Zhang Y^#. Comparison and optimization of CRISPR/dCas9/gRNA genome-labeling systems for live cell imaging. Genome Biology, 2018, 19: 39. DOI: 10.1186/s13059-018-1413-5

Lu GQ*, Duan JZ*, Shu S, Wang XX, Gao LL, Guo J, Zhang Y^#. Ligase I and ligase III mediate the DNA double-strand break ligation in alternative end-joining. Proc Natl Acad Sci U S A, 2016, 113: 1256-1260. DOI: 10.1073/pnas.1521597113

Duan JZ*, Lu GQ*, Xie Z, Lou ML, Luo J, Guo L, Zhang Y^#. Genome-wide identification of CRISPR/Cas9 off-targets in human genome. Cell Research, 2014, 24: 1009-1012. DOI: 10.1038/cr.2014.87

Zhang Y*, McCord RP*, Ho YJ, Lajoie BR, Hildebrand DG, Simon AC, Becker MS, Alt FW^#, Dekker J^#. Spatial organization of the mouse genome and its role in recurrent chromosomal translocations. Cell, 2012, 148: 908-921. DOI: 10.1016/j.cell.2012.02.002

Chiarle R*, Zhang Y*^#, Frock RL*, Lewis SM*, Molinie B, Ho YJ, Myers DR, Choi VW, Compagno M, Malkin DJ, Neuberg D, Monti S, Giallourakis CC^#, Gostissa M^#, Alt FW^#. Genome-wide translocation sequencing reveals mechanisms of chromosome breaks and rearrangements in B cells. Cell, 2011, 147: 107-119. DOI: 10.1016/j.cell.2011.07.049