The research of Haidong Dong, M.D., Ph.D., is focused on cancer immunology and immunotherapy. 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.
Dr. Dong's early work addressed the Hellstrom paradox — an enigma in tumor immunology — the coexistence of immune cells and growing tumors. He co-discovered B7-H1 (also named PD-L1) in 1998 and was the first to define a role of B7-H1 in cancer immune evasion and coined the concept of B7-H1 blockade therapy of cancer in 2002. This discovery provided an explanation for the Hellstrom paradox: Despite being surrounded by immune cells in tissues, tumor cells can escape the immune attack by using B7-H1 to dampen the function of immune cells.
Currently, the focus of Dr. Dong's research is on defining the molecular and cellular mechanisms of action of tumor-reactive T cell responses, and identifying cell intrinsic mechanisms responsible for tumor resistance to cytotoxic therapy or immunotherapy. This translational research is expected to deliver new biomarkers to predict and monitor patient responses to cancer immunotherapy, new therapeutic targets to overcome tumor resistance to immunotherapy, and new rational combined cancer therapy.
Dr. Dong's research is funded by the National Institutes of Health and Mayo Clinic.
- Defining the mechanisms of T cell responses to therapies in patients with advanced cancer. 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. Dr. Dong's research group is addressing the therapeutic impact (surgery, radiation and chemotherapy) on the patient's own immune system, and seeking a way to promote and maintain a strong anti-tumor immunity in patients following conventional treatments.
- Identifying biomarkers for cancer immunotherapy. Immune checkpoint therapy with PD-1 or PD-L1 (B7-H1) blockade has emerged as an effective therapy for many advanced cancers. Only a small fraction of patients, however, achieve durable responses. Major challenges remain, such as how to identify these responsive patients and how to monitor tumor-reactive T cells 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.
- Identifying new mechanisms responsible for cancer resistance to cytotoxic therapy. Development of resistance to therapy is a hallmark feature of human cancer. Since most cancer treatment induces cell death in cancer cells (cytotoxic therapy), cancer cells gradually and adaptively gain mechanism to survive under cytotoxic therapy. Traditionally, the emergence of chemoresistance and immunoresistance are considered as parallel and unrelated events. However, recent studies indicate that the overexpression of some immune checkpoint molecules (B7-H1/PD-L1) not only negatively influences anti-tumor immunity but also renders tumor cells resistant to chemotherapeutic agents. Dr. Dong and his team are dissecting the mechanism by which B7-H1 governs tumor chemoresistance and developing new rational combined therapies to overcome drug resistance in cancers.
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.