Research Highlights

  • Lieping Chen - The Chen lab has made novel observations on the role of CD137, on both anti-tumor memory T cells and other cells, in promoting immune-mediated tumor rejection and prevention (Blood). His group has also identified a potential role for CD137 in the immune pathogenesis of hepatitis B-induced cirrhosis and hepatocellular carcinoma (JI). Dr. Chen has continues his pioneering and translational work on B7H1 (PD-L1) modulation in tumor immunity. A Phase I clinical trial with a fully human monoclonal anti-PD-1 has been completed with meaningful responses seen in melanoma, RCC, and lung cancers (JCO). Finally, Dr. Chen has found that in humans, B7-H2 (ICOS-L), is an agonist for CD28 and CTLA-4 (Immunity).
  • David Schatz - The Schatz lab continues its interest in the functions of the RAG and AID genes, both of which contribute to lymphomagenesis and have been recently implicated in development of other cancers including CML and colon cancer. Recent work has used CHIP to identify the binding patterns of RAG1 and RAG2 and mechanisms of RAG targeting (publications in JEM and Cell). Dr. Schatz is a prior recipient of YCC pilot grant funding for this work.
  • Warren Shlomchik - Dr. Shlomchik’s lab continues work on mechanisms of GVHD and GVL. Three publications in this period defined the roles of B cells (BBMT), Langerhans cells (Blood) and TLR/inflammasome/type I IFN activation (JI) in GVHD. A fourth publication, in review, demonstrates that conventional and plasmacytoid dendritic cells are not required for GVHD induction. Dr. Shlomchik’s group continues to investigate the application of leukemia-reactive memory T cells created by donor vaccination to augment GVL and improve immune reconstitution. His clinical trial testing the hypothesis that the selective infusion of memory T cells will promote immune reconstitution with less GVHD has enrolled 8 patients (7 at the Fred Hutchinson Cancer Research Center; 1 at Yale). In collaboration with Mark Shlomchik, his group continues to investigate the mechanisms whereby memory T cells are less capable of causing GVHD.
  • Richard Bucala - The Bucala lab’s efforts are directed at understanding the role of the innate cytokine MIF in the inflammatory pathogenesis of human tumors as well as its role as a survival and proliferative factor in different tumor cells. Toward the later goal, Dr. Bucala continues a collaboration with Prof. Idit Shachar at the Weizmann Institute to better understand how the MIF receptor, CD74, which is overexpressed in human CLL functions to promote oncogenic progression. In CLL cells, MIF engagement of CD74 triggers an intramembrance cleavage that leads to the transport of the CD74 intracellular domain into the cell nucleus to initiate Rel-dependent transcriptional activation. This process further activates Syk and Akt kinases. These findings have been extended to show the coordinate involvement of a c-Met dependent signaling pathway. A similar CD74 signal transduction pathway was operative in normal colon epithelium and colon carcinoma cells. Together with the Bill Jorgensen group in Yale’s Department of Chemistry, Dr. Bucala is developing small molecule antagonists of the MIF-MIF receptor interaction. These novel compounds are being assayed in human melanoma in studies performed together with Marcus Besenberg and David Stern, and in breast cancer cells with Mike DiGiovanna. Two such MIF inhibitors show potent inhibition of chemoresistant human ovarian cancer stem cells (in collaboration with Gil Mor).
  • Mark Shlomchik- Dr. Shlomchik’s lab has two projects of high relevance to the CIRP. One is his ongoing studies of graft vs. host disease (GVHD), carried out in collaboration with Warren Shlomchik. Drs. Shlomchik have made excellent progress in characterizing a new TCR Tg model of GVHD. This has allowed them to track the fate of GVHD-inducing T cells and to compare directly memory (TM) and naïve (TN) T cells for GVHDinducing capacity. They found that TM cells were markedly impaired in their ability to cause GVHD, though they engrafted. They accumulated as well as TN except in colon. Progeny of TEM showed reduced proliferation and their expansion was inhibited by co-transfer of naïve T cells. They also developed less effector function. These studies were submitted for publication and are now in revision at Blood. Recent data suggests that at least part of the defect in TEM can be reversed when PD-1 signaling is interrupted. Mark Shlomchik’s second related project has to do with the germinal center (GC), the major site of B cell transformation in lymphoma. His lab has been doing basic studies to understand how B cells are selected and regulated in the GC. They have found that GC B cells interact with GC T cells via the PD-L2/PD-1 system to enforce the differentiation of follicular helper T cells, which in turn via IL-4 and IL-21, promote normal survival of GC B cells, a finding which was recently published. Other ongoing projects include investigation of B cell receptor signaling in the GC and of the roles of receptors important for stem cell homeostasis in the development and maintenance of the GC.
  • Mario Sznol - Dr. Szol continues to be a leader in the clinical testing of immune modulatory agents in cancer. In particular he leads studies on PD-1 and CTLA-4 blockade and an agonist antibody against CD137. He was the lead author on a recent abstract (ASCO) demonstrating efficacy of anti-PD-1 in lung carcinoma.
  • Ann Haberman - By tracking fluorescent, antigen-specific T and B lymphocytes Dr. Haberman’s group has defined the anatomic context and cellular interactions that immediately precede and instruct B cell commitment to the GC lineage. Expression of Bcl-6, a transcriptional repressor required for both GC B cell and T follicular helper (Tfh) cell differentiation, was seen in both cell types in the inter-follicular zones containing paracortical sinuses 2-3 days post immunization. Long-lived contacts between specific B and T cells were observed by intravital two-photon microscopy during this time period. Interestingly, large numbers of proliferating B cells were also observed immediately adjacent to the subcapsular sinus (SCS) of lymph nodes, but these B cells lacked Bcl6 expression suggesting that these cells may have committed to a separate, non-GC fate (Immunity, in press).
  • Ruslan Medzhitov - In the past year the Medzhitov lab has investigated the mechanisms involved in macrophage-tumor interactions. It is becoming increasingly appreciated that macrophages can play a tumor
    promoting role, although the mechanisms involved are poorly defined. His lab has found that tumor-associated macrophages sense tumor cell derived metabolites that induce the expression of VEGF and promote macrophage polarization into M2 phenotype that has tissue reparative/remodeling functions. Analysis of the pathways involved revealed the role of HIF-1a activation pathway in this response. Dr. Medzhitov is now investigating the role of this interaction in tumor promotion by macrophages.
  • Michael Girardi - The Girardi laboratory focuses on the (1) immunoregulation of carcinogenesis and (2) identification of novel therapeutic strategies for cutaneous T cell lymphoma (CTCL). Using various mouse
    mutants and complimentary laboratory models of tumor initiation and promotion via cutaneous chemical application and ultraviolet radiation exposure, Dr. Girardi is elucidating the contributions of local immune cells (gd T cells, Langerhans cells, CD8+ T-pro) to carcinogenesis. To increase our understanding of the genes regulating the behavior of CTCL cells, Dr. Girardi is studying high-resolution gene copy and expression analyses.
  • Madhav Dhodapkar - The Dhodapkar lab is interested in studying the cross talk between tumor cells and the host in the context of human myeloma. Recent studies from the lab have focused on immunity to stem cell associated antigens in humans, understanding mechanisms linking inflammation and genetic instability in human cancer, novel pathways regulating myeloma bone disease and osteoporosis, and biology of lipid reactive natural killer T (NKT) cells in humans. Current / recent clinical studies are trying to activate NKT cells in humans, evaluate the effect on immune-modulatory drugs on cellular immunity, and develop models to better understand the progression of MGUS to clinical myeloma.
  • Jordan Pober - The Pober lab has studied the mechanisms by which T cells can be recruited to peripheral sites of non-self antigen expression such as that produced by a primary or metastatic tumor. His group has found that human microvascular endothelial cells, which can display processed antigenic peptide/MHC complexes on their luminal surface, use presentation of antigen to trigger TCR-mediated capture and transmigration of antigen-specific effector memory T cells (JI). T cells that are recruited by this method are activated whereas T cells recruited by chemokines are not. Pericytes, which surround the endothelial cells of the microvasculature, can also display peptide/MHC complexes. Unactivated T cells that encounter their cognate antigen on human pericytes become anergic whereas those that are already activated (on endothelium) may become further activated. Anergy is, at least in part, due to PD-1 ligands expressed on the pericyte. Blockade of PD-1 ligands may therefore avoid anergy of chemokine-recruited effector memory T cells.