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Faculty active in this area of research are listed below. For a brief description of their research interests, click on their name in the list. Clicking on the name at the beginning of the brief description links to their detailed personal website.

Katie Alexander, PhD, Dept of Medicine, Division of Gastroenterology
Susan L. Bellis, PhD, Department of Cell, Developmental and Integrative Biology
Fred "Ted" Bertrand, PhD, Department of Clinical and Diagnostic Sciences
Donald J. Buchsbaum, PhD, Department of Radiation Oncology
R. Pat Bucy, MD, PhD, Department of Pathology
Jessy Deshane, PhD, Department of Medicine
Craig Elmets, MD, Department of Dermatology
Vithal K. Ghanta, PhD, Department of Biology
G. Yancey Gillespie, PhD, Department of Surgery
Zdenek Hel, PhD, Department of Pathology
Hui Hu, PhD, Department of Microbiology
Judith A. Kapp, PhD, Department of Ophthalmology
Christopher Klug, PhD, Department of Microbiology
Lawrence S. Lamb, Jr., PhD, Department of Medicine
Jianmei Wu Leavenworth, MD, PhD, Department of Neurosurgery
Lyse A. Norian, MD, PhD, Department of Nutritional Sciences
Lalita Samant, PhD, Department of Pathology
Lewis Zhichang Shi, MD, PhD, Department of Radiation Oncology
Yang Yang, MD, PhD, Department of Pathology
Nabiha Yusuf, PhD, Department of Dermatology

Katie Alexander, PhD H. pylori infection is firmly established as a risk factor for the development of gastric adenocarcinoma, but relatively little is known about how its colonization of the stomach contributes to epithelial dysfunction, particularly at the stem cell level. My current research project uses stem cell organogenesis to examine H. pylori infection in the human stomach and determine whether infection upregulates epithelial ST6Gal-I expression, a glycosyltransferase that is overexpressed in multiple mucosal cancers including ovarian, pancreatic and colonic. In another project, I have uncovered a dysregulation of ST6Gal-I expression in Barrett’s esophagus, a pre-cancerous lesion that is associated with an increased risk of developing esophageal adenocarcinoma. Furthermore, I also am interested in the epigenetic regulation of mucosal cancers.

Susan L. Bellis, PhD The Bellis laboratory has two principal areas of research interest:

Role of receptor glycosylation in conferring a stem-like, apoptosis-resistant cell phenotype
Our laboratory has determined that the ST6Gal-I glycosyltransferase adds a sialic acid to a distinct subset of receptors, thereby imparting an undifferentiated cell phenotype. Using cell model systems and genetically engineered mice, we have shown that ST6Gal-I-mediated sialylation controls the function of select integrins, growth factor receptors and death receptors. Collectively these molecular pathways direct intracellular signaling cascades that regulate the migration and survival of both immune cells and epithelial tumor cells. In the case of tumor cells, upregulation of ST6Gal-I confers a cancer stem cell phenotype, and accelerates metastatic progression in animal models. The broad goal of our research is to elucidate the mechanistic basis for sialylation-dependent receptor signaling, and to determine whether manipulating sialylation levels can be used as a clinical treatment for pathologies such as autoimmune disorders and metastatic cancer.

Biomimetic scaffolds for bone repair
The goal of this project is to create bone-like synthetic matrices for bone regeneration using technologies such as electrospinning and 3D printing. The composite scaffolds produced by our group support robust mesenchymal stem cell survival and proliferation, and also stimulate substantial new bone formation when implanted into bone defects. To further enhance the osteoinductive properties of the substrates, the matrices are being functionalized with tissue regenerative factors such as PDGF and BMP-2. In complementary studies, we are developing novel methods for improving the bonding of bioactive proteins and peptides to bone-mimetic scaffolds. Our broad objective is to synthesize regenerative scaffolds that, when implanted, stimulate recruitment and osteoblastic differentiation of the patient’s mesenchymal stem cells, leading to accelerated bone regeneration.

Fred "Ted" Bertrand, PhD Studies in Dr. Bertrand's laboratory focus on Notch-receptor signaling. Historically, Dr. Bertrand has been interested in the role that Notch-1 and Notch-2 receptor signaling may play during normal and malignant B-cell development, and the potential role for dysfunctional Notch in epithelial tumors such as those of the prostate and colon. In more recent studies, we have focused on a potential interplay between Notch-signaling, diet, and regulation of fat depots.

Donald J. Buchsbaum, PhD Dr. Buchsbaum’s research is focused on the use of agonistic monoclonal antibodies that bind to the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors for cancer therapy in combination with chemotherapy agents or radiation. The research involves investigation of the mechanisms of enhanced cytotoxicity produced by combination treatment with TRAIL death receptor antibodies and chemotherapy or radiation therapy. Orthotopic and metastatic breast, ovarian, and pancreatic cancer xenograft models are being used to optimize therapeutic regimens. In collaboration with investigators from the Divisions of Gynecologic Oncology and Clinical Immunology, surgical specimens from patients with ovarian cancer are being utilized to develop a tumor slice assay to attempt to correlate in vitro cytotoxicity sensitivity to treatment with death receptor antibody and chemotherapy to patient survival following treatment with humanized antibody and taxol/carboplatin. If successful, this could be used as a predictive assay to select patients for treatment. We are also investigating the use of small molecule modulators of apoptosis to increase the level of tumor cell killing. Other research involves investigating the mechanism by which basal-like triple negative breast cancers are sensitive to death receptor antibody treatment, and the response of basal-type breast cancer stem cells to treatment with TRAIL receptor antibodies, gamma secretase inhibitors, and chemotherapy.

R. Pat Bucy, MD, PhD Dr. Bucy is interested in the regulation of immune responses by T cells, particularly the forms of regulation that develop in vivo in situations with chronic antigen presence. Conventional experimental systems have used model antigens given in discreet inoculations so that the clearance of antigen is the dominant overall control mechanism. In physiological situations such as solid organ transplantation, chronic viral diseases, and organ specific autoimmune diseases, antigen is usually not cleared, but the immune system develops various control mechanisms that limit immune damage. In addition to his role as the Director of the UAB Medical Scientist Training Program (joint MD/PhD training), Dr. Bucy's lab is engaged in a wide range of projects with a translational focus, that span the gamut of basic mechanistic studies in mice to active design of human clinical trials. Active current projects include use of TCR transgenic mice to study murine heart transplant tolerance, analysis of T cell population dynamics in response to various forms of immunization, studies of viral and cellular dynamics in SHIV infected Rhesus Macaques, and a substantial series of studies focused on therapeutic immunization of HIV infected people and assessment of changes in immune function in these people. In all of these systems, multiple techniques are used including flow cytometry, immunohistochemistry, cell culture techniques, production of novel transgenic mice, real-time RT-PCR,. and in situ hybridization analysis of viral and cellular RNA species..

Jessy Deshane, PhD Dr. Deshane is committed to an academic career combining basic and translational research with an emphasis on inflammatory diseases of the airway. The focus of Dr. Deshane's research program is to enhance our understanding of the role of myeloid-derived regulatory cells in chronic airway inflammatory diseases. Asthma is a chronic inflammatory disease of the airways in which innate and adaptive immune cells participate as drivers of the inflammatory response. Free radical species have long been implicated as critical mediators of the asthmatic inflammatory process. Dr. Deshane's studies in a mouse model of allergic airway inflammation have established that subsets of free radical-producing myeloid-derived regulatory cells (MDRC) are master regulators of airway inflammation. They are potent modulators of both T cell responses and airway hyper-responsiveness. Dr. Deshane has identified human MDRC with similar function in bronchoalveolar lavage of asthmatics. Her current research interests are (1) to explore the free radical and cytokine/chemokine mediated mechanisms underlying the differentiation and function of myeloid derived regulatory cells in the establishment of airway inflammation and resolution of inflammation (2) to investigate MDRC- mediated regulation of the balance of Tregulatory cells and Th17 cells which control the tolerance vs inflammation (3) to understand how environmental pollutants such as tobacco smoke would impact MDRC function and contribute to exacerbation of inflammation in asthmatic smokers. These studies will provide insight into the role of MDRC in tobacco related pathology of the lung.

Craig A. Elmets, MD Dr. Elmets’ research focuses on the interaction of environmental agents with the skin. His research has particular relevance to skin cancer and cutaneous allergic reactions. In the area of skin cancer, his interests are on skin cancer chemoprevention and therapy. He has played a key role in defining the mechanisms by which the immune system controls the development of skin cancers. More recent studies have centered on the identification of new agents that can protect against skin cancer and on the non-surgical treatment of these malignancies. These include the arthritis drug celecoxib and extracts of green tea. He has also played a major role in the development of photodynamic therapy as a treatment for cancer. Photodynamic therapy utilizes light activated drugs to eradicate cancer. Dr. Elmets’ other area of research is on allergic contact dermatitis, of which poison ivy is the best-known example. He is evaluating better and more accurate diagnostic techniques for contact allergies. His studies have shown that certain proteins called cytokines are synthesized in skin cells from allergic individuals exposed to contact allergens but not in those obtained from people who are the not allergic. These findings provide the conceptual framework for the development of a diagnostic test for skin allergy testing, which can used by physicians and by industry as an alternative to animal testing prior to the introduction of new products into the marketplace.

Vithal K. Ghanta, PhD The research interests of our group are the treatment of cancer at multiple modality levels, quantitation of tumor load, follow-up of the response of tumors to different agents and modalities, understanding the interactions between the immune and central nervous systems, and the changes that take place in the immune system with age. I am interested in developing new approaches for the treatment of cancer, including combination treatments like passive therapy, immune stimulation, and chemotherapy. Secondly, our group has developed a conditioning paradigm for an increase in natural killer cell and cytotoxic T-lymphocyte activities. The model is used extensively in our laboratory to study the mechanisms of central nervous and the immune system interactions and the mechanisms of conditioned regulation of tumor growth.

G. Yancey Gillespie, PhD The main thrust of Dr. Gillespie's research is to develop and test specific therapies for treatment of malignant brain tumors in adults and children. One current focus is construction of replication conditional herpes simplex viruses that are both oncolytic for glioma cells and express foreign therapeutic genes. Gene transfer includes both pro-drug converting enzymes and cytokines under different promoter systems. Pro-drug enzyme systems currently being studied are cytosine deaminase (CD) alone or as a fusion protein with uracil phosphoribosyl transferase (UPRT) and purine nucleoside phosphorylase (PNP). A second focus involves studies with the CD and CDUPRT systems in both replication incompetent adenovirus and conditionally replication competent adenovirus. Adenoviruses targeted to cell surface receptors on glioma cells are being constructed to provide tumor specificity. Cytokines expressed from replication competent HSV that are being studied include TNFa, IL-2, IL-4, IL-5, IL-10, IL12, IL-16. These systems are validated by in vitro assays first before being advanced to safety and efficacy assessment in a variety of murine models of intracranial malignant gliomas. These models include transplantable intracranial gliomas of human origin (in immunocompromised scid or nude mice) or mouse origin (in syngeneic conventional mice). Dr. Gillespie's group also has acquired 2 transgenic glioma mouse models and use high-field strength (8.5T) magnetic resonance imaging to detect and monitor tumor growth in transgenic mice. One intriguing observation is the fact that many of these viral oncolytic and transgene therapies are markedly enhanced by modest doses of whole brain irradiation. This phenomenon is being studied at the cellular and molecular levels to determine how it can be best employed as a therapeutic strategy. Vectors that are to be advanced to clinical trials are tested for neurotoxicity in non-human primates. Finally, small peptides that exert an anti-angiogenic effect on tumor neovasculature or that induce apoptosis in human glioma cells are being studied as therapeutic agents in vitro and in animal models of malignant brain tumors.

Zdenek Hel, PhD Innate immune regulatory activity and neutrophil dysregulation as a driving mechanism of pathogenesis in HIV-1-infection. . Recent evidence demonstrates that neutrophils, the most abundant nucleated immune cell population in the body, play an important role in the regulation of adaptive and innate immune systems. We have shown that neutrophils from HIV-1-infected individuals display an activated phenotype, specific transcriptional profile, and increased rate of degranulation. We propose that HIV-1 infection is associated with altered myeloid cell homeostasis resulting in changes in the population frequency and functional activity of diverse granulocytic populations. Dysregulation of granulocytic recruitment, function, and clearance contributes to the pathogenesis of cardiovascular and liver diseases associated with HIV-1 infection. Specifically, neutrophils in the blood of HIV-1-infected individuals express high levels of PD-L1 that is induced by HIV-1 virions and products of microbial translocation including lipopolysaccharide (LPS). Neutrophil PD-L1 levels correlate with the expression of PD-1 on CD4+ and CD8+ T cells, elevated levels of neutrophil degranulation markers in plasma, and increased frequency of low density neutrophils expressing the phenotype of granulocytic myeloid-derived suppressor cells (G-MDSCs). Neutrophils purified from the blood of HIV-1-infected patients suppress T cell function via several mechanisms including PD-L1/PD-1 interaction and production of reactive oxygen species (ROS). The accumulated data suggest that chronic HIV-1 infection results in an induction of immunosuppressive activity of neutrophils characterized by high expression of PD-L1 and an inhibitory effect on T cell function. This newly identified mechanism of immune suppression mediated by neutrophils may alter our understanding of HIV-1 pathogenesis. Furthermore, we have shown that neutrophils from HIV-1-infected individuals display high capacity to undergo NETosis. Production of neutrophil extracellular traps (NETs) likely contributes to increased risk of cardiovascular and liver diseases in HIV-1-infected individuals.

Neutrophils and cancer. Our research focuses on neutrophils and granulocytic myeloid-derived suppressor cells (G-MDSCs), cell populations that have been recently identified to play a critical role in the regulation of adaptive and innate immune responses in cancer and chronic inflammatory conditions. Production of neutrophil extracellular traps (NETs) by neutrophils contributes to increased risk of cardiovascular and liver disease in cancer patients.

The impact of hormonal contraceptives on HIV-1 acquisition and transmission. Safe and effective methods of contraception represent a critical component of preventive health care reducing maternal and infant mortality, especially in women living in resource-limited settings. Depot medroxyprogesterone acetate (DMPA; Depo-Provera) is a highly effective progestin-based contraceptive and one of the most commonly used contraceptives in sub-Saharan Africa. Several epidemiological studies indicate an association between the use of DMPA and an increased risk of HIV-1 infection. Modelling studies indicate that the use of injectable contraceptives may be responsible for hundreds of thousands of new HIV-1 transmissions annually. It is therefore critically important to identify safe forms of contraception without a significant deleterious effect on systemic and mucosal immune environment. We demonstrated that medroxyprogesterone acetate (MPA) suppresses antigen- immune function of T cells and dendritic cells via direct and indirect mechanisms and increases the rate of HIV-1 proliferation. In a clinical study performed at UAB, we analyzed vaginal biopsies and various immune parameters in the blood of women using various forms of hormonal contraceptives. We showed that the use of MPA is associated with thinning of vaginal epithelial wall and decreased production of IFN-α by plasmacytoid dendritic cells. We have shown that MPA reduces defense mechanisms of genital epithelium by suppression of factors critical for the barrier function and structural integrity of the vaginal and cervical epithelium. Decreased production of these factors reduces the resistance of genital epithelial tissue to microabrasions and increases the probability of HIV-1 transcytosis and transmigration leading to an exposure of target cells in the parabasal epithelium and lamina propria. Furthermore, DMPA and NuvaRing (etonogestrel) significantly suppress the cervicovaginal levels of principal anti-HIV-1 inhibitory factors human β-defensin 2 and 3 and secretory leukocyte protease inhibitor (SLPI). In a recent randomized clinical study in Lusaka, Zambia, we showed that administration of MPA decreases the production of several factors in the cervicovaginal fluid of HIV-1-infected women that may contribute to higher shedding of the virus and potentially to increased rates of viral transmission. In search for safe contraceptives, we have demonstrated that norethisterone (NET) and levonorgestrel (LNG) do not inhibit the function of dendritic cells and T cells and therefore represent safe potential alternative to DMPA.

Hui Hu, PhD  Utilizing a broad variety of techniques including cellular immunology, molecular biology, biochemistry, gene-targeting (knockout and knockin), functional genomics and in vivo animal models, the Hu laboratory is interested in identifying novel regulatory genes and transcriptional networks that play critical roles in regulating the adaptive immunity. One of the research projects in the Hu laboratory is to study T follicular helper (Tfh) cells and germinal center (GC) responses (Nat. Immunol. 2014). The complex regulation that determines the initial development of Tfh cells, their developmental progression in germinal centers, and their fates after an immune response dissolves, is still not fully understood. The Hu laboratory is interested in identifying novel pathways underlying the differentiation of Tfh cells in humoral responses and designing new strategies to manipulate humoral responses for treatment of infectious diseases and autoimmune disorders. The Hu laboratory is also working to find ways to activate T cells under immunosuppressive circumstances. The Hu laboratory has demonstrated that cell-intrinsic signaling pathways are required to maintain mature T cells in a quiescent state. If these pathways are disrupted, resting T cells become aberrantly activated even in the absence of antigen challenge (Nat. Immunol. 2011). The Hu laboratory is interested in identifying regulatory genes and pathways that actively restrain T cell activation, and defining the roles of such negative regulatory pathways in controlling T cell quiescence, effector responses, memory maintenance, and tumor immunology.

Judith A. Kapp, PhD Dr. Kapp's research focuses on identifying mechanisms of inducing and abrogating immunological tolerance. Our long-term goal is to translate our findings into novel therapies for preventing graft rejection and augmenting tumor immunity.

Dr. Kapp's ongoing, studies are directed to basic and clinical aspects of immune regulation by T cells. We have recently focused on the regulatory role of γδ T cells in tolerance. Depletion of γδ T cells prevents tolerance as measured by antibody, CD4+, and CD8+ effector T cell responses induced by oral administration of antigen (Ke, Y., K. Pearce, J. P. Lake, K. Ziegler, and J.A. Kapp. J. Immunol. 158:3610-3618, 1997). To determine whether intraepithelial γδ T cells in the small intestine play a role in oral tolerance, her group has cloned them and found that they are highly immunosuppressive (Kapp, J.A., L.M. Kapp, K.C. McKenna, and J.P. Lake. Submitted). These observations suggested that γδ T cells play a critical, active role in tolerance induced by orally administered antigen. Their studies also show that the immunoregulatory role of γδ T cells is not limited to oral tolerance but extends to systemic tolerance induced by delivery of antigen into the anterior chamber of the eye (Xu, Y. and J.A. Kapp. Immunol. 104:142-148, 2001; Xu, Y. and J.A. Kapp. Invest. Opthalmol. Vis. Sci. 43:3473-3479, 2002), an immunologically privileged site.

Dr. Kapp and colleagues are interested in whether γδ T cells might also play a role in the failure of the immune system to control tumor growth in spite of the fact that many tumors express specific antigens. The failure of tumors to stimulate effective immune responses has been attributed, in part, to their lack of co-stimulatory molecules. Tumors lacking co-stimulatory molecules may induce tolerance rather than immunity leading to progressive tumor growth. As a model system, we used the ovalbumin (OVA) transfected EL4 tumor, called E.G7-OVA, which grows progressively in syngeneic mice even though it can be rejected if the mice are immunized with OVA in adjuvant. E.G7-OVA grew more rapidly in immunodeficient Rag-1 knockout mice than in immunocompetent mice suggesting that normal mice make an abortive immune response to this tumor. Depletion of γδ T cells augmented the ability of mice to reject E.G7-OVA. Moreover, spleen cells from normal, but not IL-10 knockout, mice reconstituted rapid tumor growth in γδ T cell-deficient mice. Thus, we conclude that γδ T cells play an important role in preventing immune elimination of this tumor by a mechanism that directly or indirectly involves IL-10 (Ke, Y., L.M. Kapp, and J.A. Kapp. Cell. Immunol. 221:107-114, 2003).

To test whether E.G7-OVA induced tumor-specific tolerance in the presence of normal γδ T cells, the group used drug therapy to ablate the tumors before testing for tolerance. The alkaloid, noscapine, was used because it has been determined to be a novel anti-mitotic drug that induces tumor regression (Ye, K., Y. Ke, N. Keshava, J. Shanks, J.A. Kapp, R.R. Tekmal, J. Petros, and H.C. Joshi. Proc. Nat. Acad. Sci. 95:1601-1606, 1998). Noscapine, given parenterally or in the drinking water, induces apoptosis of E.G7-OVA and causes regression of this tumor without adverse effects on normal tissues or inhibition of immune responses (Ke, Y., K. Ye, H.E. Grossniklaus, D.R. Archer, H.C. Joshi, and J.A. Kapp. Cancer Immunol. Immunother. 49: 217-225, 2000). These results form the basis of a Provisional Patent Application (No. 60/057,037).

The majority of tumors in the mice that received noscapine disappeared and did not return during continuous treatment with the drug. After four months, the surviving mice and untreated control B6 mice were injected with OVA in adjuvant to test whether the tumor had induced tolerance to OVA. The noscapine treated mice developed OVA antibody and CD4+ T cell responses equivalent to normal mice but OVA-specific CD8+ CTL responses that were 10- to 30-fold greater than the responses of controls. Although these results do not allow determination of whether the tumor induced tolerance in the absence of noscapine, they raise the interesting possibility that noscapine may have potent adjuvant activity for CTL in addition to its anti-mitotic effects. Dr. Kapp is particularly interested in testing the efficacy of noscapine in the treatment of other types of tumors. In addition, her group is investigating the possibility that its adjuvant effects may promote tumor specific immune responses using CD4+ and CD8+ T cells from transgenic mice expressing OVA-specific TCR to track specific cellular interactions in vivo using the same approach that we used for studying ocular tolerance (McKenna, K.C., Y. Xu, and J.A. Kapp. J. Immunol. 169:5630-5637, 2002). If noscapine serves as an adjuvant, it may be used clinically to augment endogenous immune responses in tumor bearing recipients or in conjunction with tumor vaccines. Augmentation of anti-tumor immunity would be particularly valuable in preventing metastasis of the original tumor or re-emergence of a dormant tumor.

Christopher Klug, PhD   Dr. Klug's laboratory focuses on a number of interrelated projects that deal with the genetic control of hematopoietic stem cell (HSC) self-renewal and differentiation and how normal developmental programs are subverted in the context of acute leukemias. They are also interested in understanding the underlying molecular events that control lineage commitment decisions within the hematopoietic system. The regulatory factors that are under current investigation for controlling lymphoid-lineage specification from HSC include the interleukin 7 receptor, early B-cell factor and Pax5. Acute leukemia is studied by introducing commonly observed chromosomal translocations into mouse stem cells using retroviral vectors. Two of the translocations that we have modeled in mice, the inv(16) and the t(8;21), are found in 25% of acute myeloid leukemia (AML) cases in man. AML accounts for 80% of all human acute leukemia and is thought to be a disease that is sustained by an abnormal HSC population that also bears the translocation. In a recently published paper, we have shown that the t(8;21) translocation causes HSC to expand in vivo to numbers that are 30-fold greater than what is typically seen in normal mice. Current efforts are underway to understand how the t(8;21) is affecting HSC self-renewal using microarrays and RNA interference technologies. The group is also beginning to use animal models to test the efficacy of novel treatment approaches to acute leukemia.

Lawrence S. Lamb, Jr., PhD Dr Lawrence Lamb is a Clinical Laboratory Immunologist and Associate Professor of Medicine specializing in transplantation immunology. He also is boarded by the Oncology Nursing Certification Corporation for Advanced Practice in Oncology Nursing (AOCNS). Dr. Lamb directs the UAB Cellular Therapy and Immunodiagnostics Laboratory and is Associate Director of the UAB Hospital Hematopoietic Stem Cell Transplantation Facility. His group was the first to describe an association between gamma/delta T cell recovery and disease-free survival in allogeneic bone marrow transplantation patients as well as gamma/delta T cell receptor CDR3 conservation in leukemia patients. He currently directs a research program for evaluation and translation of innate immune system-based therapies for Glioblastoma Multiforme and is funded by the NINDS (5R21NS57341), NCI (2 P50 CA097247- SPORE developmental project), and holds the National Brain Tumor Society’s Samuel Gershon Leadership Chair for Glioblastoma Research for 2007-2009. The laboratory has recently published that gamma/delta T cell numbers are significantly reduced in GBM patients and their function is substantially impaired (Bryant et al, Neuro-Oncology 2009 e-pub ahead of print), although activated gamma/delta T cells from healthy volunteers are highly cytotoxic to GBM cell lines and primary tumors. In a recently submitted manuscript we also show that GBM lines and primary tumors express several NKG2D ligands that are recognized and by gamma/delta T cells and that immunodeficient mice bearing human GBM intracranial xenografted tumors show improved survival when treated with ex vivo activated gamma/delta T cells. The laboratory is currently exploring receptor-ligand interactions between GBM and gamma/delta T cell subsets, the role of CMV in the innate response to GBM, and the design of an effective cell therapy product for clinical trials of gamma/delta T cell immunotherapy of GBM.

Jianmei Wu Leavenworth, MD, PhD Dr. Leavenworth's main research interest is to understand the mechanisms of self-tolerance, focusing on molecular and cellular elements that regulate effector and regulatory cell subsets of the immune response. Her long-term goal is to seek effective strategies for cancer immunotherapy using mouse models and specimens from patients with malignant tumors, including gliomas.

Lyse Norian, PhD Immune-based therapies have shown tremendous clinical potential for treating advanced cancers in a subset of patients, but their broad clinical efficacy remains limited. As obesity is a known risk factor for increased cancer prevalence and mortality, it is critical to understand how obesity impacts anti-tumor immunity and immunotherapeutic efficacy. A major research focus in my lab is investigating how immune responses to solid tumors change in the presence of chronic, diet-induced obesity. We have found that in mice with renal tumors, obesity impairs protective anti-tumor immunity and leads to immunotherapeutic failure. We are now identifying the mechanistic basis for this failure, and have already described obesity-dependent defects in CD8+ T cells, dendritic cells, and myeloid-derived suppressor cells in mice with renal tumors. To better understand the broad applicability of our findings, we are extending our studies into murine models of metastatic breast cancer. In addition, we have begun to investigate the ways in which obesity alters immune responses in renal cancer patients. Finally, as our long-term goal is to apply the fundamental knowledge gained during the course of these studies into novel, immune-based therapies for advanced cancer patients, we also have an active line of research that seeks to develop new combinatorial immunotherapies for metastatic cancers. Our pre-clinical studies in this area use in vivo imaging of localized and disseminated tumor cells in lean and obese mice to track therapeutic responses in real time.

Lalita Samant, PhD Over the past 12 years, I have been involved in education, teaching, and academic mentoring in leadership roles that include serving as the Director of the Cancer Biology Theme of Graduate Schools at two Universities, in addition to serving as a course director for multiple and diverse graduate-level courses. I am actively engaged in training and mentoring graduate students and fellows. My research program is centered on understanding the role of developmental signaling in metastasis and resistance to DNA damage. My lab has made seminal contributions to defining the role of Hedgehog signaling in breast cancer metastasis, in particular, establishing its role in determining osteolytic metastasis of breast cancer. Ongoing research is centered on defining a role for Hedgehog signaling in re-programming the immune microenvironment to establish a mutually sustaining synergy between breast tumor cells and immune cells.

Lewis Zhichang Shi, MD, PhD Identifying novel targets to improve immune checkpoint blockers. Our recent studies (Cell and Nature Communications, 2016) and previous reports demonstrated that immune checkpoint blockers (ICBs) (e.g., anti-CTLA-4) exert similar functional outcomes to those of common metabolic pathways (e.g., mTOR) (JEM and Immunity, 2011), i.e., promoting effector T cell (Teff) function (IFN-γ production) and depleting regulatory T cells (Treg). Interestingly, these effects are selectively induced in the tumor microenvironment , a special metabolic milieu with numerous features impacting the mTOR pathway. Given this key information, whether ICBs engage the mTOR pathways and its downstream targets in tumor- infiltrating T cell (TILs) is largely unknown and targeting these metabolic checkpoints as novel approaches to enhance therapeutic efficacy of ICBs remains to be explored. We will combine genetic mouse models with specific deletion of those genes in T cells, genetic manipulations with retroviral overexpression and CRISPR-CAS9 deletion, pharmacological approaches with metabolic inhibitors and activators, transplantable and orthotopic tumor models, and adoptive T-cell therapy (another promising modality in cancer immunotherapy) to evaluate therapeutic value of targeting these metabolic targets as a standalone therapy, or in combination with ICBs and conventional radiotherapy and chemotherapy. Further, we have an ongoing study showing that co- stimulatory molecule ICOS has an indispensable role in maintaining the survival and functionality of adoptively transferred tumor antigen-specific CD8+ T cells, especially when combined with ICBs. Currently, agonistic anti-ICOS therapeutic antibodies are being tested in Phase I clinical trials. Further mechanistic understanding will help guide these clinical trials and offer rationales to test additional combination therapies.

Functional and transcriptional control of T cell development and differentiation. The mTOR pathway is a master regulator for T cell metabolism, differentiation and function, with prominent roles in cancer, autoimmunity, and vaccination for infectious diseases. While the downstream targets of mTOR have been extensively studied, its upstream regulators are under-studied and an answer to which may offer potential therapeutic targets for various pathologies. Interestingly, TCR signaling regulates both Gfi1 expression and mTOR activity, suggesting Gfi1 and mTOR might crosstalk with each other. We will examine whether Gfi1 serves as an upstream regulator of the mTOR signaling. How the Gfi1-mTOR interaction dictates T cell development and acquisition of effector functions will be assessed using genetic mouse models and mouse autoimmune disease and tumor models. We recently showed that Gfi1 is required for anti-tumor immunity (PNAS, 2013) and for T cell maturation (PNAS, 2017). This study will offer new insights into whether mTOR pathway is the downstream link.

Yang Yang, MD, PhD Dr. Yang’s research focuses on multiple myeloma and tumor microenvironment, including bone microenvironment and bone marrow immunity, myeloma-induced bone diseases, and translational research on multiple myeloma. These studies are documented in over 60 publications and book chapters.

Nabiha Yusuf, PhD Our laboratory is involved in evaluating the effect of environmental influences such as chemical carcinogens and ultraviolet radiation on the skin immune system. The focus of our research is on the role of innate immunity in the development of skin carcinogenesis. Toll-like receptors (TLRs), one component of innate immunity, are intricately associated with a number of dermatologic conditions. We have found that the innate immune system mediates through Toll like receptor-4 (TLR4) signaling to activate the cell mediated adaptive immune response against chemically induced tumors. TLR4 signaling had a protective effect against 7,12-dimethylbenz(a)anthracene (DMBA) induced skin cancer in certain strains of mice which develop cell mediated immune response to this chemical carcinogen. We are currently in the process of evaluating the role of innate immune system in ultraviolet B (UVB) radiation induced skin cancer. The mechanisms by which UVB radiation influences cell-mediated immune responses have been the subject of extensive investigation.  However, there is little information on the role of innate immunity in this process. Our recent experiments suggest that certain components of innate immunity, especially TLR4, may play an important role in photoimmunosuppression. Currently, we are investigating whether the resistance of TLR4 gene knockout mice to UVB-induced immunosuppression has implications for photocarcinogenesis.  The ultimate goal of these studies will be to define the role of TLR4 in the development of immune suppression and tumor development that occurs following UV radiation.  This may allow us to identify genetic loci that are involved in these processes and to develop immunopreventive and immunotherapeutic approaches towards them.