John M. and Mary Jo Boler Associate Professor, Department of Biological Sciences
The Center for Rare and Neglected Diseases
Tumor Microenvironment, Tumor Immunity and Immunotherapy, Metastasis, Multi-Omics
Understanding and targeting the tumor microenvironment is at the forefront of current basic and translational cancer research. Targeting tumor microenvironment is closely related to tumor immunology and immunotherapy, one of the most exciting and rapidly evolving areas of cancer research. An intense focus of research in our lab is to investigate the molecular and cellular mechanisms underlying the cancer-tumor microenvironment crosstalk, in particular interactions between cancer cells and the myeloid compartment, in both primary tumors and metastases to bone and other organs. We propose that the efficacy of immune checkpoint blockade drugs (e.g. anti-CTLA4, anti-PD1 antibodies) on refractory metastatic cancer can be potently enhanced when combined with other therapy modalities, including targeted therapy that specifically antagonize immunosuppressive activities yet preserve T cell functions in the tumor microenvironment. Recent publications from the Lu lab firmly establish that immunosuppressive neutrophils (also known as polymorphonuclear myeloid-derived suppressor cells, PMN-MDSCs), play the predominant role in inducing the exhaustion of effector T cells in the tumor microenvironment across multiple solid tumors. A number of mechanisms and targeting strategies of PMN-MDSCs have been reported by the Lu lab including the CXCR1/2 inhibitor SX-682, the tyrosine kinase inhibitor cabozantinib, and the cyclooxygenase-2 inhibitor celecoxib, which may open new avenues to sensitize advanced malignancies to immune checkpoint blockade therapy. Dr. Lu also investigates and develops novel immuno-therapeutics and molecularly-targeted therapeutics, including antibody-drug conjugates, chimeric antigen receptor (CAR)-engineered NK cells and small molecules targeting transcription coactivators that promote metastasis. Through creating new models of immunosuppressive neutrophils and animal models with key genes knocked-out in neutrophils, we are on the path to identify more specific and potent therapeutic strategies on the “bad” immune compartment of solid tumors.
We investigate both cancer-cell-intrinsic and -extrinsic mechanisms of immune evasion and immunotherapy resistance. Our research has revealed a number of targetable mechanisms on how the oncogenic signaling in neoplastic cells (“cancer-cell-intrinsic”) exerts the cell non-autonomous functions to control the cancer-immune interactome in solid tumors. For example, our publication is Science Immunology (2023) found that cancer cell expression of the chromatin effector Pygo2 promotes immunotherapy resistance by restraining tumor T cell infiltration and cytotoxicity. To make these findings, we employ diverse types of models and techniques, such as genetically engineered mice and cell models, functional genomics, experimental therapeutics, and cutting-edge experimental and computational methodologies (single cell RNA-seq, spatial transcriptomics, high-throughput drug and CRISPR/cas9 screen, molecular digital pathology, multi-omics integration, etc.).
We are equally interested in the most prevalent cancer types that both women and men suffer from (breast, prostate, pancreas, kidney), as well as rare cancer types such as penile cancer and Von Hippel-Lindau disease (VHL). As part of the Center for Rare and Neglected Diseases (CRND), our mission is to understand and eliminate cancer in the near future through bench-to-bedside translational research and partnership with drug discovery powerhouses.
Our research is supported by federal grants, private foundations and institutional funds. We are actively recruiting graduate students, postdoctoral fellows and undergraduate students, who are passionate about transforming cancer medicine to benefit human health and society. Please email Dr. Lu directly if you are interested in joining us!