Tumor Immunology

 

Jason Cyster 

Malignancy of germinal center B cells is a frequent cause of lymphoma. We have characterized a novel tumor suppressor pathway involving S1PR2, Ga13 and ArhGEF1, that is frequently disrupted in germinal center B cell-derived lymphoma. We are studying how disruption of this pathway contributes to growth and dispersal of lymphoma cells. Our studies on immune cell migration also have direct relevance to understanding how we can better equip effector lymphocytes to attack tumors.

Other Research in Dr. Cyster's Lab:

Diabetes and AutoimmunityDevelopment and DifferentiationImmune RegulationImmune Response to Microbial Pathogenesis 

 

Larry Fong 

Our program is focused upon defining the immune response to tumor antigens in order to develop potential vaccine and immunotherapeutic strategies. Currently, our research program is divided into three distinct but interrelated areas of interest. These include studying dendritic cell biology, exploring approaches to break tolerance against self-antigens, and characterizing effector and memory T cells following tumor immunotherapy. 

Dendritic cell function

Dendritic cells (DC) are known to be comprised of multiple subsets (e.g. myeloid DC, plasmacytoid DC), each of which may have distinct functions. By studying different DC subsets in the context of malignancy, we hope to develop approaches to use DC as a means of inducing therapeutic antitumor immunity in vivo in both animal models and cancer patients. 

Tolerance to tumor associated antigens

The majority of the current tumor-associated antigens represent self-antigens that are either aberrantly or overly expressed by the malignancy. As a result, the vast majority of solid tumors are not immunogenic. We are using mouse and human models to define the antigen specificity of anti-tumor immune responses that either occur spontaneously or are induced with immunotherapy.

Evaluating antigen-specific T cell responses 

We have demonstrated that in vivo expansion of CD8 T cells identified with MHC/peptide tetramers can correlate with tumor responses in cancer patients. Current efforts underway are to characterize the T cell response following vaccination against tumor associated (self) antigens utilizing novel assays that couple tetramer staining (antigen-specificity) with T cell function. Moreover, we are currently characterizing the immune response not only within the blood, but also within the tissues and tumors in order to examine the distribution of an immune response. By identifying the dynamics of antigen specific T cells and their capacity to develop immunologic memory, we hope to develop improved strategies in tumor immunotherapy. 

 

Matthew Krummel 

The lab is currently using advanced imaging to visualize T cell activation in tumor draining lymph nodes and effector sites. We are generating two models—one for breast cancer and one for melanoma—in which the tumors are fluorescent. Interactions between tumors and T lymphocytes are revealed uing fluorescent dyes, including GFP fusions.

Other Research in Dr. Krummel's Lab:

Autoimmunity Immune RegulationImmune Receptors and Signaling 

 

Lewis Lanier 

NK cells have the ability to recognize and kill transformed cells without prior immunization (Lanier, Nat. Med. 2001). The NKG2D receptor expressed on NK cells and CD8+ T cells recognizes a family of MHC class I-related proteins, which includes in humans the MICA, MICB, and ULBP proteins and in mice the RAE-1, H60 and MUTL1 proteins. (Cerwenka et al., Immunity. 2000). These NKG2D ligands are generally not expressed on normal, health tissues in adults; however, they are frequently over-expressed by many types of tumors. Expression of NKG2D ligands on tumors can initiate NK cell activation and result in tumor rejection (Cerwenka et al., Proc Natl Acad Sci. 2001). Current studies in our lab focus on the NKG2D ligands, as well as other NK receptors that have been implicated in anti-tumor immunity.

Other Research in Dr. Lanier's Lab:

HIV and Viral ImmunityDiabetes and AutoimmunityImmune Receptors and Signaling

 

Will Seaman 

Our laboratory is interested in the receptors that activate or inactivate natural killer (NK) cells, which spontaneously kill tumors.

Other Research in Dr. Seaman's Lab:

Allergy and AsthmaImmune Receptors and SignalingImmune Response to Microbial Pathogenesis 

 

Matthias Wabl 

The genes that are necessary for normal, controlled cell growth are called tumor suppressor genes, and inactivation of these genes can lead to tumor formation. The majority of known tumor suppressors were located by the genetic mapping of organisms with an inherited predisposition for cancer. However, familial predisposition to cancer is responsible for only approximately 10% of human cancers and identification of tumor suppressors involved in non-familial cancers has been slower. The goal in the lab is to define the set of tumor suppressors that when deleted contribute to the formation of lymphocyte tumors in mice; and their interactions with protooncogenes, as completely as possible.

We define cancer genes by retroviral insertional mutagenesis, combined with chemical mutagenesis, to inactivate both alleles in cells of a given mouse. The offspring of chemically mutagenized male mice are subjected to insertional mutagenesis by retrovirus that induces tumors of lymphocyte origin. The viral genome disrupts potential suppressor genes, leading to their inactivation, and at the same time creates a marker for identifying the insertion loci. The tagged cancer genes are cloned and sequenced. In collaboration with several other labs, we characterize a subset of the cancer genes and determine the nature of their cooperation with other oncogenes (co-mutations).

Other Research in Dr. Wabl's Lab: 

Development and DifferentiationImmune Receptors and SignalingInflammation 

 

Zena Werb 

It is now widely recognized that the inflammatory microenvironment of mutated tumor cells is a major determinant of malignancy in cancers. The host response to tumorigenesis includes the recruitment of innate and acquired immune cells.  Cells of the myeloid lineage, such as macrophages, neutrophils, mast cells, and myeloid suppressor cells are major components of the complex microenvironment of neoplastic cells in solid tumors. We are using transgenic mouse models of breast cancer and intravital microscopy to investigate the mechanisms by which inflammatory and immune cells enhance mammary tumor development by regulating angiogenesis, tumor growth, tumor dissemination and metastasis and by suppressing the anti-tumor immune response. We are also studying how tumor cells recruit the immune cells to the tumor and metastatic sites.

Other Research in Dr. Werb's Lab: 

Inflammation Development and Differentiation