The Wang Lab works to understand the immune suppressive tumor microenvironment to identify novel combination immunotherapeutic approaches to glioblastoma and GI metastases.

Wang Lab

The Wang Laboratory's research interests are in elucidating the immune suppressive tumor microenvironment to identify novel combination immunotherapeutic approaches to glioblastoma and GI metastases as well as in using synthetic lethality and monoclonal antibodies for cancer therapeutic development.

Research Interests

illustration shows single cell spatial transcriptomics with rare cells, macrophage cell states and immune checkpoints highlighted

Develop novel therapeutic approaches targeting brain cancer, with emphasis on glioblastoma

Glioblastoma (GBM) remains the most lethal disease with a very dismal outcome and there were many failed phase 3 trials on both targeted therapy as well as immunotherapy. We have recently developed several experimental approaches to tackle the complexity of GBM at the genomic, epigenetic and tumor microenvironmental levels. We will explore the state-of-the-art single cell sequencing technology (CosMx and 10X vasium platform) to elucidate the cell-cell interactions in the tumor microenvironment. We have recently established a role of TBK1 in macrophage polarization and we will further explore inhibiting TBK1 in sensitizing immunotherapy against GBM. EGFRviii is one of the most prevalent oncogenes for GBM but there is no targeted therapy available. We have also established EGFRviii GBM animal model and the role of EGFRviii in tumor microenvironment remodeling and epigenetic landscape will be explored to define novel therapeutic approach.

illustration of de novo resistance to anti-PD-1 therapy

Overcome resistance to immunotherapy

Since only a subset of cancer patients benefitted from immunotherapy, there is a growing need to identify predictive biomarkers and intrinsic resistance mechanisms to improve clinical efficacy. We recently developed a network approach which has successfully identified genes and pathways known to be associated with anti-PD1 response (Wu et al., Nature Comm 2022). We found that MHC1- association prediction uncovered ~2000 genes showing strong correlation with immune infiltration using the TCGA Pan Cancer data. On average, about 400 genes were identified in a given cancer type. Five distinct cancer types (GBM, prostate, melanoma, colon, and pancreatic) will be screened by targeted CRISPR libraries in vivo for sensitizers to PD1 treatment. Additional bioinformatic approach will be explored to identify sensitizers for other immune checkpoints.

bioinformatic analysis of prostate adenocarcinoma

Synthetic Essential approach to identify and validate synthetic lethal targets in human cancers

Given the successful SE approach in targeting tumor suppressors (Zhao et al., Nature 2017; Lee et al., Cancer Discovery 2022), we have performed additional bioinformatic analyses and compiled a putative list of genes that we will screen for key tumor suppressor loss in major cancer types, including GBM, PDAC, prostate cancer. We will further test whether such approach can be extended to target oncogenic fusion events that are not druggable, such as the ETS fusions in majority of prostate cancer patients. CRISPR screening will be performed followed by validation in appropriate animal models.

Additional funded projects

We have identified KDM5D as a male specific gene which mediates Kras driven colon cancer metastasis. We will elucidate the role of KDM5D in CRC progression and to define KDM5D target genes in mediating the metastasis process. We have also established KDM5D transgenic mice in a colon cancer model and its role will be further investigated in vivo.

In collaboration with Dr. Chun Li at MD Anderson Cancer Center, we will focus on the effect of irreversible electroporation on immunotherapy. We will explore a combination of IRE+PD1 +anti MDSC agents in pancreatic cancer liver metastasis model and tumor microenvironments will be studied post treatment using spatial transcriptomics.

Current Research Funding

NIH/NCI 1R01CA231349 (Wang, PI)
Developing Novel Therapeutic Approaches Targeting Macrophages in GBM

NIH/NCI 1R01CA258540 (Li and Wang, MPI)
Development of irreversible electroporation-based rational combinations to potentiate the activity of cancer immunotherapy against pancreatic ductal adenocarcinoma

NIH/NCI 1RO1 CA262798-01A1 (Wang, PI)
Sex specific epigenetic regulation of colon cancer metastasis.

DOD (Wang, PI)
Elucidating and therapeutic targeting of prostate bone metastasis

Recent Publications

Liao W. et al., KRAS-IRF2 Axis Drives Immune Suppression and Immune Therapy Resistance in Colorectal Cancer. Cancer Cell. 2019 Apr 15;35(4):559-572.e7. doi: 10.1016/j.ccell.2019.02.008. Epub 2019 Mar 21. PMID: 30905761; PMCID: PMC6467776.

Chen P. et al., Circadian Regulator CLOCK Recruits Immune-Suppressive Microglia into the GBM Tumor Microenvironment. Cancer Discov. 2020 Mar;10(3):371-381. doi: 10.1158/2159-8290.CD-19-0400. Epub 2020 Jan 9. PMID: 31919052; PMCID: PMC7058515.

Zhao D. et al., Chromatin Regulator CHD1 Remodels the Immunosuppressive Tumor Microenvironment in PTEN-Deficient Prostate Cancer. Cancer Discov. 2020 Sep;10(9):1374-1387. doi: 10.1158/2159-8290.CD-19-1352. Epub 2020 May 8. PMID: 32385075; PMCID: PMC7483306.

Lee R. et al., Synthetic Essentiality of Tryptophan 2,3-Dioxygenase 2 in APC-Mutated Colorectal Cancer. Cancer Discov. 2022 Jul 6;12(7):1702-1717. doi: 10.1158/2159-8290.CD-21-0680. PMID: 35537038; PMCID: PMC9262860.

Gulhati, P. et al.,Targeting T cell checkpoints 41BB and LAG3 and Myeloid cell CXCR1/2 results in anti-tumor immunity and durable response in pancreatic cancer. Nature Cancer 2022 Dec 30. PMID: 36585453

View a full list of publications

Research Team

Yaoqi Alan Wang, PhD

Paige Brown Professor of Experimental Therapeutics

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David Eisenbarth, PhD
Postdoctoral Fellow

Hyejin Oh, BA
Research Assistant

Tadahito Yasuda, MD, PhD
Postdoctoral Fellow

Simpla Mahato, PhD
Lab manager

Fei Gao, MD, PhD
Research Assistant Professor

Feng Guo, MD, PhD
Postdoctoral Fellow