Combine CRISPR screening and immunogenomics analysis to delineate tumor microenvironment heterogeneity and to characterize master regulator of tumor immune evasion –Supported by NIH/NCI 1R01CA272866 (Yang, D)

In 2015, through whole-exome sequencing tumor clonality analysis, we revealed that drug resistant gastric tumor is characterized by high levels of intra-tumor heterogeneity (PNAS, 2015). We later developed a lincRNA-based immune response (LIMER) score that can predict the immune cell infiltration and patient prognosis in multiple cancer types. (Science Advances, 2021).

In 2022, we performed a genome-wide CRISPR activation screening of 9744 lncRNAs in melanoma cells co-cultured with human CD8+ T cells. We identified 16 novel lncRNAs potentially regulating tumor immune response. Further integrative analysis using tumor immunogenomics data revealed that IL10RB-DT and LINC01198 regulate tumor immune response and immunotherapy outcome in melanoma and breast cancer (Science Advances, 2022, Fig. 1).

Most recently, we performed the first comprehensive scRNA-seq analysis of how the implanted human immune system in hCD34+ humanized mice interact with human TNBC breast cancer. Our results demonstrate that hCD34+ mice indeed mobilized a complete human immune response to xenografted human tumors. We have furthered showed that this model is an outstanding preclinical model to investigate the gene-immunotherapy and drug-immunotherapy interaction in cancer (Science Signaling, under review, Fig. 2).

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