Sixteen Outstanding Young Investigators Receive Cancer Research Institute Postdoctoral Fellowship Award

The Fellowship Review Committee of the Cancer Research Institute’s Scientific Advisory Council, with the approval of the Institute’s Board of Trustees, has named 16 new postdoctoral fellows from its April 2008 application round, awarding more than $2.3 million in research funding through the Irvington Institute Fellowship Program of the Cancer Research Institute.

The 16 young research scientists are conducting basic and tumor immunology laboratory investigations under the guidance of leading immunologists and tumor immunologists at distinguished academic institutions throughout the United States, including Harvard Medical School, Massachusetts Institute of Technology, New York University School of Medicine, The Scripps Research Institute, the University of Texas Southwestern Medical Center, the University of Washington, and Yale University, among others.  Since the fellowship program’s inception in 1971, 926 fellows have received valuable funding from the Cancer Research Institute.  Many fellows have since gone on to become leaders in their field, including two who have won the Nobel Prize.

* Project titles denoted with an asterisk have a special focus in tumor immunology

Amanda L. Blasius, Ph.D.
The Scripps Research Institute
La Jolla, California 

Project Title: Genetic analysis of the type 1 interferon response to TLR9*
Sponsor: Bruce Beutler, M.D. 

Type I interferons are signaling proteins essential for combating viral and bacterial infection, tumorigenesis, and autoimmunity.  Plasmacytoid dendritic cells are responsible for triggering immune responses by producing type I interferons.  Utilizing a unique pathway through Toll-like receptor 9 (TLR9) or TLR7, these cells produce copious amounts of interferons.  Although the general aspects of this pathway are known, many finer mechanistic details are lacking and essential components remain to be identified.  Dr. Blasius is using a forward genetics screening approach to identify and ultimately characterize novel genes that function within this pathway.  Characterizing these genes may have broader implications for immunity in general.  Ultimately, further understanding of the type I interferon response, with emphasis on TLR signaling and plasmacytoid dendritic cells, may identify new therapeutic targets for treating a wide variety of diseases, including cancer.

André Catic, M.D., Ph.D.
Massachusetts General Hospital, Harvard Medical School
Boston, Massachusetts 

Project Title: Proteome regulation in hematopoietic stem cells
Sponsor: David T. Scadden, M.D. 

Our immune system critically depends on lymphocytic blood cells.  Lymphocytes derive from bone marrow-resident hematopoietic stem cells (HSCs), which produce up to one thousand billion new blood cells of different types every day for the duration of a human life.  However, over time HSCs selectively lose the ability to create lymphocytes, increasing the chances of infections, tumors, and the risk to develop autoimmune diseases.  Dr. Catic’s research aims to discover what causes HSCs to decrease generation of lymphocytes over time.  He is comparing the composition of proteins (the proteome) inside HSCs during the course of aging.  He has already singled out several candidate proteins that are specifically increased in old HSCs and he is now investigating how these changes contribute to the age-related decrease of lymphocyte generation.  Protein production and degradation are tightly controlled by a complex network of enzymes.  Dr. Catic is also researching how these enzymes that control protein lifespan influence HSC biology.  One regulator in particular is highly active in HSCs but not in other blood cells, and it is likely that this enzyme and the proteins it controls play a pivotal role in stem cell biology.  The outcome of this work will not only tell us more about how blood-forming stem cells operate, but also about the nature of stem cells in general, including those that give rise to cancers.

Kaushik Choudhuri, DPhil
Skirball Institute of Biomolecular Medicine, NYU School of Medicine
New York, New York

Project Title: The cell biology and molecular biophysics of the immunological synapse
Sponsor: Michael L. Dustin, Ph.D. 

Antigen recognition by T lymphocytes is a central event in adaptive immune responses.  T cells recognize small protein fragments (peptide antigen) of infecting pathogens and neoplastic tissues, expressed on the surface of affected cells.  Antigen recognition takes place at the cellular interface between T cells and their targets known as the immunological synapse.  Researchers do not yet understand completely the process whereby the engagement of antigen-associated ligands by the T-cell antigen receptor (TCR) lead to appropriate cell activation.  Recent findings suggest that intrinsic binding and clustering properties of T-cell surface molecules all play a part.  Dr. Choudhuri aims to employ powerful genetic, high resolution optical imaging and structural approaches to provide a detailed view of the molecular mechanisms responsible for the induction, assembly, and signaling of TCR microclusters.  This research will provide a better mechanistic understanding of T-cell activation and the means to construct predictive models for T-cell activation.

Stephanie K. Dougan, Ph.D.
Whitehead Institute for Biomedical Research
Cambridge, Massachusetts

Project Title: The role of B lymphocytes in cross-presentation of tumor antigens*
Sponsor: Hidde L. Ploegh, Ph.D. 

Although B cells are most famous for their ability to secrete antibodies, they can also display protein fragments to T cells.  A subset of T cells, called cytotoxic, can seek out and destroy cells which have been infected with a virus or which have become cancerous.  Usually dendritic cells are responsible for the initial activation of cytotoxic T cells, but B cells could be capable of starting a T-cell response as well.  Current vaccine strategies elicit robust B-cell responses which result in production of virus neutralizing antibodies.  Antibodies alone are sufficient to protect against certain types of viruses such as measles; however, tumors or viruses which establish a latent infection require cytotoxic T cells for their removal.  Dr. Dougan intends to devise a new strategy for generating cytotoxic T cells to design therapeutic tumor vaccines.  She aims to define the role of B cells in the so-called priming stage of a cytotoxic T cell response, and to then use B cells to enhance the efficacy of a tumor vaccine in mice.  If B cells can activate cytotoxic T cells, then this pathway could be exploited to design new vaccines, including therapeutic tumor vaccines for humans.

Etienne Gagnon, Ph.D.
Dana-Farber Cancer Institute
Boston, Massachusetts

Project Title: Regulation of T-cell activation through dynamic membrane binding of the TCR-CD3 ITAMs
Sponsor: Kai Wucherpfennig, M.D., Ph.D.

The initiation of protective T-cell responses requires the recognition of pathogens or tumor cells by the T-cell receptor (TCR).  Dr. Gagnon has demonstrated that the CD3ε cytoplasmic domain of the TCR is membrane-bound in live cells, and is investigating how signals are transmitted across the T-cell membrane to the cytoplasmic signaling motifs.  The cytoplasm is where most cellular chemical reactions take place.  Biochemical studies have demonstrated that the CD3ε cytoplasmic domain binds to synthetic lipid vesicles (fat transporters), and membrane binding is reduced by mutation of the CD3ε cytoplasmic domain.  Dr. Gagnon’s studies show that the introduction of particular mutations eliminates binding.  Interestingly, treatment of cells with ionomycin (an antibiotic) substantially reduces the interaction of the CD3ε cytoplasmic domain with the membrane, which may explain why a large number of TCRs participate in signaling even when they only encounter a small amount of TCR signaling antigens.  Dr. Gagnon aims to define the physiological relevance of ITAM (activation motif) membrane binding in T-cell activation as well as the molecular mechanisms by which this interaction is regulated.  Definition of these mechanisms may enable modulation of T-cell signaling thresholds during cancer immunotherapy. 

Stacy M. Horner, Ph.D.
University of Washington
Seattle, Washington

Project Title: Hepatitis C virus controls innate immunity by targeting IPS-1 to establish chronic infection
Sponsor: Michael J. Gale Jr., Ph.D. 

Hepatitis C virus (HCV) causes both liver disease and liver cancer by blocking molecular signals to the innate immune system that otherwise would mark a virus-infected cell for immune destruction.  HCV infects approximately 170 million people worldwide, and infection is typically for life.  The innate immune response is our first line of defense against virus infection.  In the case of HCV infection, activation of this response is dependent on a cellular protein called retinoic acid inducible gene-I (RIG-I). When RIG-I senses virus inside a cell, it interacts with its binding partner, interferon promoter stimulator factor-1 (IPS-1), to signal activation of the innate immune response.  An HCV protein, NS3/4A, turns off this response during HCV infection by binding and cleaving to IPS-1 and thereby preventing it from interacting with RIG-I.  Dr. Horner aims to isolate the mechanisms by which NS3/4A targets and binds to IPS-1 prior to cleavage, and seeks to understand how these mechanisms impact the outcome of HCV infection and disease.  Results from these studies will provide novel insights into how HCV controls the innate immune response during infection.  This, in turn, may lead to new strategies to reactivate the innate immune response upon HCV infection and, thus, reduce the incidence of HCV-associated disease and liver cancer.

Da Jia, Ph.D.
UT Southern Medical Center
Dallas, Texas

Project Title: The role of lysine methylation in regulating the actin cytoskeleton
Sponsor: Michael K. Rosen, Ph.D.

Understanding T-cell signaling is critical in the development of anti-cancer therapies that seek to manipulate T-cell responses to cancer.  Rapid progress over the last decade has identified many regulators of the actin cytoskeleton, a structure that undergoes rearrangement during T-cell activation.  The protein lysine methyltransferase Ezh2 adds a methyl group (a small chemical entity) to specific positions in certain proteins during cytoskeleton rearrangement.  This activity of Ezh2 has been found to be essential for actin polymerization and cell signaling in T cells and several other cell types. Emphasizing the importance of Ezh2 in this process is the observation that over-expression of Ezh2 is associated with a variety of cancers.  However, the exact target of Ezh2 in actin regulatory pathways is unknown and the role of methyl addition remains unclear.  Dr. Jia will identify which pathways are modified by Ezh2 and dissect the biochemical mechanism by which methyl addition controls signaling to actin.  This study will deepen our understanding of actin dynamics in immune cells, identify the specific role that methyl addition plays in regulating actin in particular, and add new insights into T-cell receptor signaling and immune response.  The new understanding could reveal new targets for novel tumor immunotherapy and lead to new treatments for cancer that act on methyl addition in actin regulatory pathways.

Shari M. Kaiser, Ph.D.
Institute for Systems Biology
Seattle, Washington

Project Title: A proteomics approach to identify and characterize determinants of pathogenicity in highly pathogenic influenza
Sponsor: Adrian Ozinsky, M.D., Ph.D. 

Influenza A is a simple virus that has the potential to manipulate our immune system to its advantage in order to grow and spread.  Recently, a new strain of Avian Influenza (Bird Flu) has crossed into the human population with an extremely high death rate in those people infected.  Dr. Kaiser is exploring what this version of Influenza is doing to the immune system that makes it so deadly, and is also examining the common features between the immune pathways that detect infection and those that sense cellular alterations occurring during cancer.  Much like viruses, malignant cells are adept at subverting the immune system both by modulating immune sensors and evading immune surveillance.  Dr. Kaiser aims to exploit the simple genetics and tractable manipulation of the Highly Pathogenic Influenza virus, (H5N1), to identify and characterize cellular targets of the viral proteins known to antagonize and manipulate immune sensors and effectors.  These key regulators will also be critical to the complex role of inflammation in cancer progression. 

Prashant Kodgire, Ph.D.
The University of Chicago
Chicago, Illinois

Project Title: Transcription, chromatin, and AID in somatic hypermutation of Ig genes
Sponsor: Ursula Storb, M.D. 

Somatic hypermutation (SHM) is a process of radical, randomized genetic mutation that generates a vast diversity of antibodies that are essential for health.  This process is initiated by the enzyme cytidine deaminase AID and is linked to initiation of genetic transcription, in which information on DNA is copied to another molecule, RNA.  However, it is not known whether somatic hypermutation requires the process of transcription itself.  A cell’s chromatin consists of the DNA and associated proteins called histones.  The location of a core of histone proteins on chromatin plays an important role in genetic transcription, and defines the boundaries of active and silent chromatin.  The role of the histone proteins in the regulation of SHM of antibody genes has not been investigated and Dr. Kodgire will investigate how AID acts in the antibody genes.  His experiments are important for determining how the varied repertoire of antibody genes is created with the potential to react against any foreign antigenic substance, including tumor cell antigens.  Besides aiding the defense against tumors, SHM can have a negative effect as a promoter of cancer by giving rise to B-cell lymphomas and leukemias.  Thus, understanding somatic mutation will aid in the investigation of the cellular, genetic, and environmental causes of B-lymphocyte malignancies as well as in learning how to influence the production of high affinity antibodies against infectious agents and tumors.

Blythe Duke Sather, Ph.D.
Children’s Hospital and Regional Medical Center
Seattle, Washington

Project Title: Role for PKC-beta over-expression in the development of B-cell lymphomas*
Sponsor: David J. Rawlings, M.D. 

Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoma and accounts for 30-40 percent of all new diagnoses of adult non-Hodgkin’s lymphoma.  Many studies have identified molecular factors associated with reduced responses to therapy and poor survival of DLBCL patients, but some of this work is conflicting.  Dr. Sather is analyzing biochemical changes that occur during lymphoma development to evaluate the mechanistic role of different molecular changes.  A transcription factor called NF-κB is essential for the survival and activation of normal B cells.  Specific kinases, particularly protein kinase C-beta (PKC-beta), are essential for NF-κB activation and link signals from the B-cell receptor to downstream gene transcription. A decreased amount of PKC-beta leads to B-cell defects, while an over-expression of PKC-beta is associated with clinically unmanageable DLBCL.  Dr. Sather is attempting to delineate PKC-beta and its downstream components’ contributions to tumor differentiation and survival.  Her studies may lead to new therapeutic targets to treat DLBCL patients that do not respond to current treatments.

Isabel Scholz, Ph.D.
Vaccine and Gene Therapy Institute, Oregon Health and Sciences University
Beaverton, Oregon

Project Title: Analysis of a novel rhesus cytomegalovirus immune evasion mechanism*
Sponsor: Klaus Früh, Ph.D. 

Even though the immune system is on constant alert to find and destroy malignant cells, a variety of mechanisms protect them from death.  Cytomegaloviruses, very successful pathogens, are amazingly adept at concealing themselves from immune recognition by blocking a process called antigen presentation.  Antigen presentation signals to immune surveillance cells that a particular cell is malfunctioning and needs to be destroyed.  One of the proteins needed for this process is termed MHC-I.  Cytomegaloviruses exhibit well-characterized mechanisms of degrading MHC-I molecules before they can reach the surface of cells, minimizing the danger of detection.  The laboratory of Dr. Klaus Früh has discovered a completely novel mechanism used by rhesus cytomegalovirus to interfere with MHC-I functioning.  Determining the exact molecular mechanism will lead to insights not only about how the viral protein acts, but also about the basic cellular mechanism of MHC-I synthesis, processing, and transport.  This will also contribute to our knowledge about how malignant cells interfere with MHC-I antigen expression and thereby evade destruction by the immune system.

Rashu Bhargava Seth, Ph.D.
Yale University
New Haven, Connecticut

Project Title: Targeting high-fidelity and error-prone DNA repair pathways during somatic hypermutation
Sponsor: David G. Schatz, Ph.D. 

DNA mutations caused by external chemical and environmental agents have long been associated with cancer.  Dr. Seth’s research focuses on understanding a cellular genetic process called somatic hypermutation (SHM) that is capable of introducing mutations within DNA.  The normal/physiological function of SHM is to improve a B-cell immune response by introducing mutations within antibody gene segments to generate antibodies that bind tightly to pathogens.  The introduction of mutations by SHM depends on the action of ‘error-prone’ DNA repair pathways.  SHM can also be initiated at many non-antibody genes.  Most of these genes do not accumulate mutations because they are repaired by high-fidelity or ‘error-free’ repair pathway.  Dr. Seth’s study will help identify important factors that control the function of these repair pathways in cells and inform how cells control the activity of SHM so that it does not create havoc in the genome by mutating non-antibody genes.  Further, the results of this experiment will address the possibility that a break-down in the repair pathways involved in SHM leads to disease conditions like cancer.

Selvakumar Sukumar, Ph.D.
University of California at Berkeley
Berkeley, California

Project Title: Identification of chromatin modifying factors that regulate V(D)J recombination
Sponsor: Mark S. Schlissel, M.D., Ph.D. 

B cells recognize microbes and their toxins using a diverse set of antigen receptors called immunoglobulins (Ig’s). Genes encoding Ig’s are assembled from gene segments through a coordinated process termed V(D)J recombination. V(D)J recombination is tightly regulated by proteins, called RAGs, that recognize and cut DNA at specific signal sequences that flank Ig gene-segments. Genes exist as chromatin (DNA wrapped around protein structures called nucleosomes), and although the structure and covalent modifications of chromatin are believed to regulate RAG access to the DNA and thus V(D)J recombination, very little is known about the mechanistic details. Nucleosomes positioned over signal sequences are used to impede RAG access and Dr. Sukumar’s study will investigate how this apparent barrier is overcome to allow V(D)J recombination. Defective regulation of V(D)J recombination results in chromosomal translocations, which are a major cause of leukemias and lymphomas. Hence, a thorough knowledge of the mechanisms that regulate V(D)J recombination will help us better understand and prevent these blood cancers.

Tim Willinger, M.D., Ph.D.
Yale University School of Medicine
New Haven, Connecticut

Project Title: Role of dynamin 2 in T-cell homeostasis and trafficking
Sponsor: Richard A. Flavell, Ph.D. 

Homeostasis keeps the number of T cells within the body under tight control.  Loss of T cells can lead to immune deficiency (e.g., HIV) and an excess of T cells can lead to immune attack against our own body (autoimmunity).  T cells continuously patrol our body to detect foreign invaders, a process called trafficking.  The regulation of T-cell homeostasis and trafficking is poorly understood at the molecular level.  Dr. Willinger has identified one protein called dynamin 2 as very likely to be essential to these processes as well as to modulating the backbone of the cell, the actin cytoskeleton.  The actin cytoskeleton is important for cell movement and cell communication.  However, the physiological function of dynamin 2 in T cells is almost completely unknown.  Results show that the absence of dynamin 2 leads to a dramatic reduction in T cells and to abnormal distribution of T cells within the body.  This strongly suggests a novel and essential role of dynamin 2 in the survival and migration of T cells and has broader implications for a variety of human diseases where the immune system is involved.  It is also highly relevant for the development of immunotherapies against infectious diseases and cancer.

Erbay Yigit, Ph.D.
Northwestern University
Evanston, Illinois

Project Title: Effect of nucleosome positioning on regulation of gene expression
Sponsor: Jonathan Widom, Ph.D. 

Proper regulation of gene expression is essential for normal cell development and differentiation.  The chromatin structure within the cellular nucleus is a dynamic series of DNA packaging units called nucleosomes that plays an important role in the regulation of gene expression by modulating the “on” and “off” state of genes.  The location of nucleosomes along the DNA controls the access DNA binding proteins have to their target sites.  Researchers have shown that the density of nucleosomes along the DNA undergoes regulated changes during normal development, and many nucleosomes move to new locations as cells undergo specific differentiation.  Abnormal changes in nucleosome density are associated with several types of cancers, including erythroleukemia.  Dr. Yigit’s research will seek to increase our understanding of the exact mechanism of how DNA binding proteins regulate the expression of their target genes.  His discoveries will provide deeper insights into the genetic mechanisms of cancer cell development and immune cell differentiation, and will potentially aid in the development of effective cancer therapies.

Matthew J. Youngman, Ph.D.
Massachusetts Institute of Technology
Cambridge, Massachusetts

Project Title: Genetic dissection of innate immunity during aging in C. elegans
Sponsor: Dennis H. Kim, M.D., Ph.D. 

The underlying causes of a decline in immune function later in life, termed immunosenescence, are poorly understood.  By investigating age-related changes in the immune system of the roundworm Caenorhabditis elegans, Dr. Youngman hopes to uncover the basis for immunosenescence.  Worms are protected from infection by proteins that recognize or kill pathogens, and mechanisms exist to carefully control when these proteins are made.  Two proteins called PMK-1 and DAF-16 act as switches to turn on the processes leading to the synthesis of different sets of proteins that combat infection.  Results indicate that, whereas the function of PMK-1 may become less important over time, DAF-16 plays an increasingly pivotal role in immunity during aging.  This observation leads to the hypothesis that immunosenescence is caused by differences in the activity of PMK-1 and DAF-16 later in life.  During old age, innate immune dysfunction can lead to chronic inflammation, which is thought to promote many types of cancer.  Therefore, Dr. Youngman’s studies of age-associated factors involved in the modulation of PMK-1 and DAF-16 may have implications for our understanding of tumor progression and in the possible development of cancer therapies.