The research of Haidong Dong, M.D., Ph.D., is focused on defining regulatory mechanisms that influence anti-tumor immunity. The long-term goal of his laboratory is to understand the molecular and cellular regulatory mechanisms in tumor-immune cell interactions and translate basic research observations into effective cancer immunotherapies.
Two main factors contribute to the failure of tumor immunity: First, the immune system is rendered ineffective by the overwhelming presence of tumor cells; second, tumor cells develop resistance to immune responses. The focus of Dr. Dong's research is on understanding how the immune system progressively loses its effectiveness in eliminating tumor cells and how tumor cells acquire resistance to multiple treatments.
To achieve its research goals, Dr. Dong's group is intensively utilizing gene targeting (knockout and knockdown) strategies, monoclonal antibody blockade/ligation, protein interaction/identification assays, microarray, nanoproteomics, multiplex cytokine assays, and flow cytometry.
Dr. Dong's research is funded by the National Institutes of Health and Mayo Clinic.
B7-H1 (PD-L1, CD274) and endogenous anti-tumor immunity. Naturally occurring (endogenous) anti-tumor immunity is present, but it is mostly invisible. Endogenous anti-tumor immunity not only prevents tumor cells from causing cancer, but also influences the outcome of growing tumors in responses to various treatments. In most cases with progressive cancers, endogenous anti-tumor immune cells remain quiescent in spite of the persistent presence of tumor antigens that are recognized by immune cells. There must be an active brake on the immune system that dampens their anti-tumor ability.
Dr. Dong co-discovered a B7 family immune regulatory molecule, B7-H1; later this molecule was renamed as PD-L1 because it was identified as a ligand of PD-1. It is also called CD274. Shortly after the discovery of B7-H1, Dr. Dong and colleagues published an observation that several human cancer cells expressed high levels of B7-H1, and blockade of B7-H1 reduced the growth of tumors in the presence of immune cells. At that time it was concluded that B7-H1 helps tumor cells evade anti-tumor immunity.
Anti-PD-1 or B7-H1 immunotherapy. After a decade of preclinical studies from Dr. Dong and others on PD-1 and its ligands in tumor immunity, it is clear that releasing the brake mounted by the PD-1 and B7-H1 immune checkpoint pathway is a promising therapeutic approach to cure cancers. As shown in many clinical trials, injection of anti-PD-1 or anti-B7-H1 antibody alone results in tumor reduction and prolonged survival of a portion of cancer patients. This led to the hypothesis that blockade of PD-1 or B7-H1 must restore or re-activate the endogenous anti-tumor immune responses in patients. It is very likely that people with cancer who have ongoing endogenous anti-tumor immune responses will respond to anti-PD-1 or B7-H1 blockade therapy.
However, major challenges remain, such as how to identify these responsive patients and how to monitor endogenous anti-tumor immune responses during immunotherapy. To address these questions, researchers in Dr. Dong's group are defining the physiological and pathological mechanisms of regulating endogenous anti-tumor immune responses. They are also developing methods to monitor the degree to which immune checkpoint blockade contributes to restoring or enhancing anti-tumor immunity.
Significance to patient care
Efforts by Dr. Dong and his team are directed toward developing strategies for improving tumor immunotherapy and blunting tumor resistance to cytotoxic therapies, such as immunotherapy, chemotherapy and radiotherapy. While their research is largely centered on tumors of the kidney, bladder, prostate and breast, as well as on melanoma, the impact of their investigations extends to leukemia and solid malignancies in general.