PROFESSOR, EPPLEY INSTITUTE
Courtesy Appointments - Department of Biochemistry & Molecular Biology, Department of Pathology and Microbiology
Ph.D. Southern Illinois University, 1992
A significant advance in the area of cancer immunology has been the characterization of tumor-associated antigens recognized by T lymphocytes. These tumor-associated antigens have been found to be peptides, derived from tumor-specific proteins, that are bound to cell surface receptors called major histocompatibility complex (MHC) molecules. Once a T lymphocyte has recognized an MHC molecule that bears a tumor peptide, it lyses the cell to prevent further spread of the malignancy. To transport a tumor peptide to the cell surface, the class I MHC heavy chain must first bind to it inside the cell, assisted by a group of proteins. Our laboratory is studying the assembly of the class I MHC molecule with peptides and the intracellular trafficking of the class I MHC molecule, with the goal of identifying ways in which those processes influences the type and quantity of tumor-specific antigens that are presented to T lymphocytes, and with the goal of increasing the expression of MHC molecules on tumors. Our laboratory has discovered that amyloid precursor-like protein 2 influences MHC class I surface expression and simultaneously affects the growth of certain kinds of cancer cells, and therefore it is a therapeutic target from both immunology and cancer biology perspectives.
We are also using the knowledge gained from our studies on T cell-mediated immunity in our development of better immunotherapies (including cytokine and chemokine immunotherapies) for cancer, as well as for infectious diseases such as influenza. For pancreatic cancer and breast cancer, new approaches to cancer therapy that can be used in conjunction with existing treatment strategies are urgently needed. As an adjunct therapeutic approach, immunotherapies can potentially be used to attack tumors regionally or systemically, with minimal side effects. Dendritic cells are the major cells responsible for initiating an effective response against tumors, via presentation of antigens from engulfed tumor cells to T lymphocytes. The localization and numbers of dendritic cells are determined by chemokines and cytokines. Dendritic cells, as well as T lymphocytes, are attracted by the chemokine CCL21, and the cytokine Fms-like tyrosine kinase-3 ligand (Flt3L) causes in vivo expansion of DCs. We are working to determine the effects of CCL21 and Flt3L on dendritic cell and T lymphocyte activity against pancreatic and breast cancers.
Examples of Specific Projects:
Effect of Endoplasmic Reticulum Proteins on Class I MHC Assembly (NIH R01 GM57428)
Assembly complex proteins such as calreticulin, the transporter associated with antigen processing, and tapasin interact with peptide-free class I heavy chains in the endoplasmic reticulum. To understand how the assembly complex regulates antigen presentation, we are defining the separate roles of each of these endoplasmic reticulum proteins in the retention of class I MHC prior to peptide loading. We are analyzing their sites of interaction with class I and their ability to respond to peptide binding by releasing class I so that it can migrate to the cell surface. These studies will yield new insights into the regulation of antigen presentation and will be helpful in the design of rational approaches for clinical treatment of cancer.
Modified forms of adenovirus are used as gene therapy vectors for the treatment of cancer. Some serotypes of non-modified adenovirus can cause gastrointestinal, respiratory, and eye infections, and some are oncogenic. This virus produces a protein, expressed in the endoplasmic reticulum, that fights back against the immune response by binding to the class I MHC molecule and preventing it from reaching the cell surface. We are studying whether this adenovirus protein blocks class I cell surface expression by displacing peptide or any of the members of the assembly complex from class I. From this information, a better understanding will be gained of not only virus/immune system interactions, but also of the binding sites and functional attributes of the normal cellular factors that interact with class I.
Regulation of Antigen Presentation by APLP-2 (NIH R21 AI054645)
Cancer patients are particularly susceptible to infections. Certain pathogens, including many viruses and bacteria, hide within cells after they enter the body. In order to develop effective vaccines and other treatments to deal with these pathogens, there is a need to understand how the immune system can recognize such infected cells and destroy them before the disease can spread within the body. Our laboratory has recently discovered that the cellular protein amyloid precursor–like protein 2 (APLP-2) affects the presentation of antigens to the immune system, and we are seeking to understand the mechanisms behind its activity. The findings from this research will contribute to our ability to prevent and treat many severe infectious diseases.
Pancreatic and Breast Cancer Immunotherapy Projects:
Pancreatic adenocarcinoma is a devastating disease, characterized by resistance to current therapies and extremely poor prognosis (median life expectancy of less than one year). Breast cancer afflicts one in eight women in America, with over 200,000 new cases arising every year. Despite advances in control of breast cancer by surgery, radiation, and chemotherapy, the 5-year survival rate for women with local/regional disease is only 78%, and patients with metastasized tumors have a 5-year survival rate of less than 25%. New approaches to cancer therapy, particularly ones that complement existing treatment strategies, are urgently needed. As an adjunct therapeutic approach, immunotherapies can potentially be used to attack tumors regionally or systemically, with minimal side effects. Dendritic cells (DCs) are the major cells responsible for initiating an effective response against tumors, via presentation of antigens from engulfed tumor cells to T lymphocytes. The localization and numbers of DCs are determined by chemokines and cytokines. DCs, as well as T lymphocytes, are attracted by the chemokine secondary lymphoid tissue chemokine (SLC). The cytokine Fms-like tyrosine kinase-3 ligand (Flt3L) causes in vivo expansion of DCs. We are working to determine the effects of SLC and Flt3L on DC and T lymphocyte activity against pancreatic and breast cancer, in combination with each other and with p53 vaccination (for breast cancer) and mutant K–ras peptide vaccination (for pancreatic cancer).
E-Mail: Joyce Solheim