Welcome to the website for Dr. Kelvin Lee and his team.
The Lee lab has two overall areas of research: (1) dendritic cell differentiation and protein kinase C (PKC) beta II and (2) multiple myeloma. Dendritic cells are critical inducers of T cell immune responses. We have previously found that PKC Beta II is essential in the process of DC differentiation. We are building on our past work by examining the role of PKC beta II down regulation on immune suppression in cancer patients and by developing PKC beta II into a novel treatment for chronic myeloid leukemia. Multiple myeloma is a cancer of plasma cells (terminally differentiated B cells). We are studying molecular and cellular mechanisms of multiple myeloma survival and plasma cell longevity, and the role of CD28 and the Jagged/Notch pathway. We are also investigating novel therapeutic strategies targeting multiple myeloma.
PKC beta II and DC Differentiation
Tumor induced immunosuppression promotes tumorigenesis and is a barrier against successful immunotherapy of cancer. One facet of tumor induced immunosuppression is inhibited dendritic cell (DC) differentiation, resulting in a dearth of this critical inducer of T cell immunity and an accumulation of directly immunosuppressive immature myeloid cells. Though a number of factors that inhibit DC differentiation have been described, the molecular basis of this phenomenon is poorly understood. Prior work in our lab has demonstrated a requirement for protein kinase C beta II (PKC βII) expression and signaling in CD34+ hematopoietic progenitor cells undergoing DC differentiation. This leads us to hypothesize that tumors may inhibit DC differentiation by down regulating PKC βII expression in myeloid progenitor cells. Matt Farren is testing this by studying the importance of PKC βII down regulation to tumor inhibition of DC differentiation and mechanisms by which tumors down regulate PKC βII expression in DC progenitor cells. He is also developing PKC beta II transgenic and conditional knock-out mice, using the Cre/loxP system, as tools to study tissue-specific functions of PKC beta II. Haley is working to identify transcription factors involved in early DC differentiation, which may manipulated by tumor-induced signaling. Understanding how these transcription factors control DC differentiation would not only lead to a better comprehension of DC biology, but also shed light on how tumor conditions can drive DCs toward an immunosuppressive state.
Dave Hoekstra and Louise Carlson are developing PKC beta II based treatments of chronic myeloid leukemia. These are designed to overcome imatinib resistance and act specifically on CML cells to induce apoptosis and DC differentiation.
The lab is also studying thalidomide and lenalidomide, which are in a class of drugs called IMiDs, named as such because of their immunomodulatory ability. They have significant clinical activity in the treatment of multiple myeloma and B cell chronic lymphocytic leukemia (CLL). However, the IMiDs do not directly kill myeloma or B-CLL cells, and their mechanism of action in these diseases remains largely unclear. It is suspected that the IMiDs somehow affect the tumor microenvironment. We have found that lenalidomide disrupts the differentiation of dendritic cells, which we have implicated as being key pro-survival elements of the multiple myeloma microenvironment. Louise Carlson is working to understand the molecular mechanisms by which lenalidomide affects DC differentiation.
Multiple myeloma (MM) is the second most prevalent hematologic malignancy after non-Hodgkin’s lymphoma in the United States. The disease is an incurable malignancy of terminally differentiated B-lymphocytes or plasma cells and is intimately associated with the bone marrow microenvironment. The lab investigates the molecular and biochemical nature of the interactions between myeloma cells and their bone marrow stromal cell (BMSC) microenvironment towards the eventual understanding of their relevance in pro-survival and drug resistance in myeloma. The lab was one of the first to recognize the role of CD28 in MM survival. Jayakumar Nair's work focuses on CD28 interaction of BMSCs and myeloma cells specifically the induction of pro-survival and immunosuppression. Cheryl Rozanski is currently working on plasma cell longevity; specifically looking at CD28 as a myeloma survival signal. She will be characterizing the cellular responses to CD28 activation; while assessing if targeting myeloma CD28 itself, components of its signaling pathway or stromal partners can be exploited therapeutically, in vitro and in vivo in a murine model.
Chandana Koorella’s work deals with understanding the molecular and cellular components of the human bone marrow stroma which aid in multiple myeloma survival. Dendritic cells are known to interact closely with myeloma cells promoting their survival. While the molecular nature of these interactions is poorly described, the Notch1-Jagged2 and CD28-B7 pathways are known to induce IL-6 production, which is a pro-survival factor for myeloma cells. She is looking into the mechanism of B7 “backsignaling”, which is unknown, and possible crosstalk between these two pathways leading to myeloma cell survival.
Megan Murray is investigating the pro-survival interactions between the CD28 receptor on multiple myeloma cells and B7 molecules on DC in the bone marrow microenvironment. Although we have demonstrated that blocking this interaction sensitizes multiple myeloma cells to chemotherapy in vivo, Megan will determine if this interaction can be targeted in vivo. If the myeloma-CD28: DC-B7 interaction can be targeted in mouse models, Megan will identify drugs that significantly reduce tumor burden and/or further sensitize myeloma cells to additional chemotherapeutic treatments.