Research Interests

The Zou laboratory has phenotypically and functionally studied different subsets of APCs in the human tumor environment - including myeloid DCs, plasmacytoid DCs, macrophages, and MDSCs. They are the first research team to demonstrate that human cancer environmental and draining lymph node APCs highly express inhibitory PD-L1 (B7-H1) and B7-H4 (B7s, B7x), and blockade of these checkpoints enhances tumor specific T cell anti-tumor immunity. The laboratory has published a series of research articles, dating as early as 2003, on these checkpoint studies in patients with cancer. These human studies have laid the foundation for current clinical application of checkpoint blockade and have impacted viewpoints on tumor immunotherapy. In addition, the Zou team has recently discovered that tumor stanniocalcin-1, a glycoprotein, impairs APC phagocytosis and T cell activation via trapping calreticulin in mitochondria. Stanniocalcin-1 serves as a phagocytosis checkpoint driving tumor immune resistance and would be a target for cancer therapy. The Zou laboratory continues their efforts in identifying new immune checkpoints in human cancers.

Tumors reprogram metabolic pathways not only to meet their bioenergetic, biosynthetic, and redox demands, but also to evade effective anti-tumor immunity. The Zou team has discovered that tumor glycolysis targets specific microRNAs and the methyltransferase Enhancer of Zeste 2 (EZH2) to alter effector T cell survival and function; and tumor glycolysis targets CCAAT/enhancer-binding protein beta (CEBPB) isoform, Liver-enriched Activator Protein (LAP) to regulate MDSC development in the tumor microenvironment. Furthermore, tumors target the Nuclear factor erythroid 2-Related Factor 2 (NRF2) -associated antioxidant system in Tregs via the oxidative pathway, causing accelerated Treg apoptosis and enhanced Treg suppressor capacity via adenosine accumulation in the tumor microenvironment. Moreover, the Zou laboratory has demonstrated that tumors, via the methionine transporter solute carrier 43A2 (SLC43A2), disrupt methionine metabolism in CD8⁺ T cells, thereby lowering intracellular levels of methionine and the methyl donor S-adenosylmethionine (SAM), and resulting in loss of dimethylation at lysine 79 of histone H3 (H3K79me2), diminished STAT5 expression, and impaired T cell immunity. Apart from glycolysis, oxidative phosphorylation, and amino acid metabolism, the laboratory is exploring a role of lipid metabolism in T cell immunity in the tumor microenvironment.

A prevailing paradigm in cancer biology was that key genetic and epigenetic mutations are both necessary and sufficient for cancer development, progression, and therapeutic resistance. It is now recognized that the immune responses play a critical role in these progresses. However, it is not well understood if epigenetic and oncogenic mutations affect T cell-mediated anti-tumor immunity. Loss of tumor-suppressive function of p53 through TP53 gene deletion or mutation is the most frequent event in human cancers. Targeting the p53–MDM2 (Mouse Double Minute 2 homolog) pathway to reactivate tumor p53 is a chemotherapeutic approach. The Zou team has shown that regardless of tumor p53 status, the p53–MDM2 pathway controls T cell STAT5 expression, thereby T cell effector function and immunity. These important insights would inform the novel design, screening, and selection of MDM2-targeted agents and the patient stratification for future clinical trials. In addition, EZH2, a component of Polycomb Repressive Complex 2 (PRC2) complex, functions as an oncogene in tumors. ARID1A (AT-Rich Interaction Domain 1A) is a core member of SWItch/Sucrose Non-Fermentable (SWI/SNF) complex. ARID1A mutations occur in many types of human cancer, including ovarian clear cell carcinoma with a 50% mutation rate. Th1-type chemokines CXCL9 and CXCL10 and effector T cell tumor infiltration are associated with cancer patient survival and correlate with clinical response to PD-L1 and PD-1 blockade in some types of cancer. The Zou laboratory has found that epigenetic elements - including EZH2, ARID1A, and DNA Methyltransferases (DNMTs) - affect Th1-type chemokines and IFN-signaling, thereby determining effector T cell tumor migration, and shaping cancer immunity mediated by the PD-L1 and PD-1 pathway blockade and adoptive T cell therapy. The data has shown that reprogramming epigenetic pathways will synergize current cancer immunotherapy. Thus, this research has revealed a mechanism that addresses why some tumors are “inflamed” (hot) and some others are “non-inflamed” (cold). This work has provided scientific rationale for a novel combinational regimen of epigenetic therapy and immunotherapy in patients with cancer. The team is exploring a role of additional members of the SWI/SNF and PRC2 complexes in T cell immunity in the tumor microenvironment.

The IFN- and MHC-signaling genes are the most critical immunogenic pathways in the tumor microenvironment. Mutations in IFN and MHC signaling genes endow immunotherapy resistance. However, most patients with cancer do not exhibit IFN and MHC signaling gene mutations. The Zou laboratory has identified key genetic mechanisms controlling the integrity of the IFN- and MHC-signaling pathways. They have discovered that LncRNA Inducing MHC-I and Immunogenicity of Tumor (LIMIT) is a previously unknown, cancer immunogenic lncRNA. LIMIT locally targets Guanylate Binding Proteins (GBPs), thereby forming a molecular cascade of LIMIT-GBP-HSF1 (Heat Shock Transcription Factor 1) to regulate MHC expression, alter T cell-mediated immunity and tumor immunotherapy efficacy. This work not only reveals novel biology of an immunogenic lncRNA, LIMIT, but also suggests that the LIMIT-GBP-HSF1 axis may be targetable for cancer immunotherapy. In addition, they have found that gradual loss of optineurin impairs the integrity of both IFNg and MHC-I signaling pathways via palmitoylation-dependent IFNg receptor (IFNGR)1 lysosomal sorting and degradation, thereby driving immune evasion and intrinsic immunotherapy resistance in colorectal cancer. The data suggests that pharmacologically targeting IFNGR1 palmitoylation can stabilize IFNGR1, enhance T-cell immunity, and sensitize checkpoint therapy in colorectal cancer. Along this line, the Zou team is exploring novel immunogenic molecular nodes in the tumor microenvironment.

Ferroptosis is a type of programmed cell death dependent on iron and characterized by the accumulation of lipid peroxides. The Zou laboratory has demonstrated that CD8⁺ T cell derived IFNg alters oxidized lipid species and inhibits Xc system (SLC7A11 and SLC3A2) in tumor cells, enhancing tumor cell ferroptosis initiated by immunotherapy, chemotherapy, and radiation therapy. The Zou team has identified that ferroptosis is a novel mode of action of cytotoxic CD8⁺ T cells (CTLs). Thus, apart from apoptosis and necroptosis, CTLs can induce tumor cell ferroptosis via distinct mechanisms. Ferroptosis was discovered studying the cytotoxic effects of small synthetic molecules, such as erastin and RSL3, in cultured tumor cells in vitro. The Zou laboratory is exploring tumor intrinsic ferroptosis initiating mechanisms and the importance of the ferroptosis signaling pathway in a variety of immune cell subsets in the tumor microenvironment.

Autophagy is a regulated mechanism that removes unnecessary or dysfunctional cellular components and recycles metabolic substrates. The Zou laboratory has found that the autophagy pathways regulate the phenotype and function of peritoneal resident Tim-4⁺ macrophages and T cells in tumor bearing mouse models and patients with cancer. Their results reveal an interplay of the metabolic and autophagy pathways in the regulation of survival and function of macrophages and T cells in the tumor microenvironment. Fusobacterium (F.) nucleatum is an oral bacterium, commensal to the human oral cavity. The Zou laboratory and collaborators have discovered that intestinal F. nucleatum targets Toll-like receptor 4 (TLR4) and Myeloid Differentiation primary response 88 (MYD88) innate immune signaling, and activates tumor autophagy pathways, thereby endowing resistance to chemotherapy in patients with colon cancer. Altogether, their work suggests that targeting the autophagy pathways may enhance and/or synergize cancer therapy, including immunotherapy and chemotherapy.