• Researcher Profile

    Gordon J. Freeman, PhD

     
    Gordon J. Freeman, PhD
     
    Professor of Medicine, Harvard Medical School

    Office phone: 617-632-4585
    Fax: 617-632-5167
    Email: gordon_freeman@dfci.harvard.edu

    Preferred contact method: email
     
     

    Research Department

    Medical Oncology/Hematologic Neoplasia

    Area of Research

    Costimulation of Lymphocyte Activation


    Dana-Farber Cancer Institute
    450 Brookline Avenue
    Dana 530
    Boston, MA 02215

    Biography

    Dr. Freeman received his PhD from Harvard University in 1979 and also joined DFCI that year. He did postdoctoral training in the laboratory of Dr. Harvey Cantor and then with Dr. Lee Nadler. Principally involved in basic laboratory research, he has studied the B7-CD28 gene family, showing that B7-2/CD28 is the major costimulatory pathway for T cell activation and that PD-L1/PD-1 is the major coinhibitory pathway for T cell activation.

    Recent Awards

    • Institute of Scientific Information highly cited researcher in Imunology, 2003
    • Fellowship, American Cancer Society, 1982
    • Damon Runyon-Walter Winchell Fellowship, 1980

    Research

    Costimulation of Lymphocyte Activation

    The capacity of the immune system to fight disease depends on the expansion and differentiation of clones of T cells that specifically attack that disease.   My work has focused on the identification and functional characterization of the B7 gene family of costimulatory molecules.  We have shown that B7-2/CD28 is the major pathway that costimulates T cell activation and PD-L1/PD-1 is the major pathway that coinhibits T cell activation.  

    B7-1 and B7-2 on antigen-presenting cells bind to CD28 on T cells to costimulate T cell activation and cytokine production. Following T cell activation, T cells express a second protein, CTLA4, that tightly binds B7-1 and B7-2 and downregulates the immune response. If T cells are stimulated through the T cell receptor in the absence of B7 costimulation, the T cells are inactivated or anergized and cannot be reactivated. By blocking B7 costimulation, physicians at DFCI have been able to induce tolerance in patients undergoing HLA-mismatched bone marrow transplantation. Conversely, increasing the B7 signal augments T cell activation so introducing B7 into tumors allows the immune system to attack tumors. 

    We discovered two new members of the B7 family, PD-L1 and PD-L2, and showed that they were ligands for PD-1.  PD-1 is a cell surface receptor structurally related to CD28 and CTLA-4 and is expressed on activated lymphoid and myeloid cells and germinal center T cells. Engagement of PD-1 by PD-L1 or PD-L2 dramatically inhibits T cell activation, cytokine production, and target cell killing. These immune inhibitory pathways have a natural role in tolerance and in preventing tissue damage by an excessive immune response.

    We made mAbs that block the PD-1/PD-1 Ligand pathway and were the first to show that antibody blockade of the PD-1 pathway enhanced T cell activation and cytokine production as well as CD8 T cell cytolysis.   PD-L1 and PD-L2 are expressed on antigen presenting cells and some normal tissues such as placenta and endothelial cells. Critically, I showed that PD-L1 is highly expressed in many solid tumors such as breast, lung, kidney, and ovarian as well as some hematologic malignancies and allows these tumors to evade immune attack. Antibodies against PD-L1 or PD-1 have been developed for tumor immunotherapy and are showing promising results in clinical trials.

    In collaboration, we discovered that in chronic viral infections, PD-1 is highly expressed on “exhausted” T cells that have lost functional activity. MAbs that blocked the PD-1/PD-1 Ligand pathway enhanced virus-specific CD8 T cell responses in vivo, resulting in increased proliferation, cytokine production, cytolytic activity, and a reduction in viral load. High PD-1 expression on exhausted T cells is a common theme seen in cancer and chronic infections including HIV, malaria, Hepatitis B and C in humans.

    We have identified an additional immune inhibitory pathway, CD160/HVEM. In addition I collaborated in the identification of a novel gene family, the TIMs (T cell Immunoglobulin Mucin) whose members are differentially expressed on the cell surface of Th1 and Th2 cells and which are genetically associated with susceptibility to autoimmune diseases such as asthma and EAE.  We showed that the TIMs were cell surface receptors for phosphatidylserine, a lipid exposed on apoptotic cells that serves as an “eat me” signal for phagocytes and a cell death “sensor” for T cells.

    These results change the way we think about antigen-presenting cells and suggest that T cell activation is the sum of activating versus inhibitory signals delivered by the antigen-presenting cell. The course of T helper cell activation and differentiation is directed by costimulatory signals provided by the antigen presenting cell. Immune activation may be increased by augmenting the B7 signal or by blocking the PD-1, CTLA4, or other inhibitory signals. Exhausted T cells with increased inhibitory receptor expression is a general feature of cancer and chronic viral diseases.  Blockade of  inhibitory receptors such as PD-1, CTLA4, CD160, and TIM3 is proving to be an effective therapeutic target for reactivating the immune response in cancer and chronic viral diseases.  Our current work focuses on understanding and manipulating these novel immunoregulatory pathways, singly and in combination.

    Trainees

    • Zhu, Baogong, MD
    • Bu, Xia, MD
    • Xiao, Yanping, PhD
    • Jones, Jennifer, MD, PhD
    • Kang, Yuhoi, PhD
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