Cancer Research Institute Names Six New Investigator Award Winners

August 4, 2008 -- The Cancer Research Institute, a nonprofit charitable organization dedicated to advancing immunology to conquer cancer, announced that the Investigator Award Review Committee of the Institute’s Scientific Advisory Council, with the approval of the Institute’s Board of Trustees, has named six new investigators from its March 2008 application round, awarding more than $1.2 million in research funding through the Institute's Investigator Award Program. 

The Cancer Research Institute Investigator Award Program aids scientists who are newly embarking on their independent academic research careers at the assistant professor level.  These awards are not tied to any specific research project.  Rather, the awards provide them the freedom to pursue promising lines of inquiry that their new responsibilities otherwise might not allow them to follow.  The aim of the program is to provide flexibility and a degree of stability in what is essentially a make-or-break period in the scientist’s life.

The six scientists are conducting basic and tumor immunology laboratory investigations at distinguished academic institutions throughout the United States, as well as in Greece and Japan.  Since the Investigator Award Program’s inception in 1986, 120 investigators have received funding from the Cancer Research Institute, including the newest winners.  CRI extends its congratulations to each of this year's award winners.

Dendritic cells, an important component of the immune system, specialize in recognizing pathogens (such as virus or bacteria) and can trigger a potent immune response from other immune cells.  Dendritic cells also play an important role in stimulating anti-tumor immunity and maintaining homeostasis of the immune system.  Their abnormal function may lead to the development of cancers and autoimmune disease (in which the immune system attacks the body’s own tissues).  Dr. Chi is investigating the Mitogen-activated protein kinase (MAPK) signaling pathway and its role in the regulation of dendritic cell development and function.  His study may lead to new dendritic cell-based therapeutic strategies for treating cancers and autoimmune diseases.

Neetu Gupta, Ph.D.  
Cleveland Clinic Foundation
Cleveland, Ohio

Project Title: Regulation of B-cell immune response by the ERM family protein ezrin

Underactive or overactive B cells are often associated with immunodeficiency, cancer, and autoimmune disorders.  When activated by its cell receptor, a B cell makes antibodies reactive to infecting bacteria and viruses, and is also prevented from reacting to its own self.  B cells respond to environmental pathogens and are also directed to sites where they can interact with T cells and receive help to make antibodies.  B-cell response involves dynamic rearrangement of its cell membrane, which in turn depends on the interaction of the membrane with the cellular skeleton.  Ezrin is one of the proteins that facilitate tethering of the B-cell membrane to the cellular skeleton.  Ezrin is also thought to participate in the communication of signals from the cell’s surface to its core, the nucleus, where gene expression occurs.  Dr. Gupta’s laboratory is investigating the dynamics of membrane cytoskeletal remodeling triggered during activation of B cells with other cells at sites of immune response.  This research will not only enhance the current understanding of B-cell activation, but also offer valuable insights into lymphocyte biology and signal transduction in general.  Ultimately, the proposed research promises a better comprehension of immunological diseases that result from interruption of signaling pathways and cellular architecture, and would enable identification of drug targets for specific and smarter therapy.

Morgan Huse, Ph.D.
Memorial Sloan-Kettering Cancer Center
New York, New York

Project Title: Quantitative image analysis of natural killer cell signaling dynamics

Natural killer (NK) lymphocytes specifically recognize and eliminate cancerous cells and cells that have been infected with viruses.  They also play a crucial role in the killing of leukemic cells after bone marrow transplantation.  NK cell activity is governed by an array of diverse cell surface receptors, some which deliver activating stimulation, and others that inhibit responses.  Studies suggest that the balance between activating and inhibitory signals dictates killing responses, but it is unclear precisely how NK cells integrate and resolve this conflicting information.  Dr. Huse is investigating this signal integration by combining synthetic chemistry with live imaging of single NK cells.  These studies will reveal, with exceptional spatial and temporal resolution, how NK cells integrate and resolve conflicting activating and inhibitory signals.  This information should contribute to strategies aimed at modulating NK cell activity to better fight cancer.

Hiroyoshi Nishikawa, M.D., Ph.D.
University Graduate School of Medicine
Tsu, Mie, Japan

Project Title: Comparative analyses of antigen specific CD4+ Th/Treg cells and Treg involvement in anti-tumor immune responses

CD4+CD25+ regulatory T cells (Tregs) are known to suppress immune responses, sometimes hampering clinical benefits of cancer vaccines in patients and are associated with poor clinical outcomes.  There is only limited knowledge of which antigens are recognized by Tregs and how/when Tregs suppress anti-tumor immune responses.  Using SEREX methodology, in which tumor antigens are identified, Dr. Nishikawa reports that specific antigens that recognize Tregs are immunogenic self-antigens present within tumor cells.  Surprisingly, these antigens are also recognized by CD4+ helper T cells (Th cells).  Still, it is unknown whether Tregs and Th cells recognize the same epitopes within the self-antigens, and whether these self-antigens contribute to the accumulation of Tregs at the tumor site.  Clarifying these questions would provide an important next step to avoid unexpected activation of Tregs by cancer vaccines aimed at inducing CD4+ Th helper cell activation.  In addition, it has recently been reported that adaptive immune responses contribute to a sustained tumor immune “equilibrium” state.  Dr. Nishikawa will address Treg involvement in the “elimination” and “equilibrium” phases of tumor immunoediting.  Together, these research perspectives should contribute to our understanding of the influence of Tregs in immunological responses to cancer.

Charalampos Spilianakis, Ph.D.
Foundation of Research and Technology – Hellas (FORTH)
Crete, Greece

Project Title: Biochemical isolation and characterization of the protein complexes that regulate interchromosomal interactions

A Locus Control Region can regulate the expression of signaling proteins on the same chromosome but can also regulate the expression of several signaling protein genes located on different chromosomes.  Dr. Spilianakis recently showed during his CRI-supported postdoctoral fellowship that the interchromosomal association of loci found on three different mouse chromosomes precedes differentiation of CD4+ T cells and acts as a checkpoint for T-cell fate determination.  These associations indicate a repressive role in non-differentiated naïve CD4+ T cells (cells that have never encountered an antigen) and an activatory role in differentiated T cells.  To further understand how these interactions are established, Dr. Spilianakis plans to use genetic and biochemical approaches to isolate, purify, and characterize the protein complexes that generate and/or maintain these interchromosomal interactions.  This research will provide substantial novel information on how the genome is shaped and how the nuclear structure affects global gene expression.  The acquired mechanistic insight could be used to study the deregulation of gene expression in disease models since the physical proximity of genomic loci increases the probability of chromosomal translocations and the creation of malignancies.

Russell E. Vance, Ph.D.
University of California, Berkeley
Berkeley, California 

Project Title: Analysis of inflammasome activation in Naip5 deficient mice

Once abnormal tissue is detected in our bodies, it can be eliminated by the immune system.  However, infected tissue or tumors can sometimes closely resemble normal healthy tissue.  Dr. Vance addresses the fundamental question of how the immune system initially distinguishes normal from abnormal tissue.  This is a critical distinction – failure to respond rapidly and appropriately can lead to damaging autoimmune diseases and cancer.  The initial decision about whether the immune system should respond to a perceived threat is made by an arm of the immune system called the innate immune system.  An important cell type within the innate immune system is the macrophage.  Dr. Vance has found that a gene called Naip5 is an important regulator of innate immune responses by macrophages.  By understanding how Naip5 functions, therapeutics can be developed that will stimulate both Naip5 and innate immune responses to attack intruders (e.g., tumors) in cases when the immune system has inappropriately ignored these intruders.