Shadmehr Demehri, Ph.D. - US grants

DESCRIPTION (provided by applicant): Asthma and atopic dermatitis are the two major allergic diseases, which are caused by chronic inflammation affecting lung airways and skin, respectively. In addition to the clinical and pathological similarities between asthma and atopic dermatitis, both complications develop frequently in the same patient, suggesting a common etiology particularly during childhood. Importantly, the recent molecular studies have identified thymic stromal lymphopoietin (TSLP) as a common initiating factor causing both disorders. TSLP is an epithelial-derived IL-7-like cytokine capable of activating dendritic cell-mediated T helper 2 inflammation, which is central in pathogenesis of asthma and atopic dermatitis. Although the molecular pathways connecting TSLP to the inflammation and disease have been studied extensively, the mechanism stimulating lung and skin epithelial cells to overexpress TSLP is not fully understood. The current dogma favors the role that allergens/pathogens may play in causing epithelial TSLP overexpression. It argues that defective epithelial-barrier function allows the invading agents to directly contact and injure the epithelial cells, inducing them to release TSLP as a secondary effect. Our recent findings, however, demonstrated that aberrant barrier formation itself serves as a potent stimulus inducing TSLP overexpression by epithelial cells. Therefore, it is intriguing to hypothesize that intrinsic epithelial differentiation/barrier formation defects that precede the need for a functional barrier, are the primary cause of TSLP overexpression by the epithelia that fail to properly differentiate. To test this hypothesis, this project will focus on a model organ that is extensively studied in our lab, the mouse skin. The proposed specific aims will examine (I) how epidermal differentiation/barrier formation defects (intrinsic factors) cause TSLP overexpression at the molecular level and (II) if barrier dysfunction (extrinsic factor(s)) is able to induce TSLP overexpression by the skin that has a transient or chronic barrier defect. Achievement of these aims will extend our recent discovery, establishing the role of environment and genetics in regulating epithelial TSLP overproduction, also identifying the signaling pathway mediating the cell autonomous aspect of such an effect. Ultimately, it will determine the relative importance of intrinsic epithelial defects in the development of asthma and atopic dermatitis, opening up a novel therapeutic approach to treat these chronic diseases. More than 20 million Americans suffer from asthma, which together with atopic dermatitis account for the majority of chronic allergic diseases affecting children and adults. Thus, better treatment for these conditions will benefit a large group of patients and significantly reduce the burden on the healthcare system.

? DESCRIPTION (provided by applicant): As the U.S. population ages, the prevalence of cancer and its impact on life span, quality of life, and healthcare costs are on the rise. While cancer treatments have greatly improved over the past several decades, they are still inadequate for many forms of cancers, indicating the urgent need for new approaches. A rapidly growing area of research with the potential to greatly improve cancer therapy is the use of immune system as an anti-tumor agent. Currently, several drugs have been developed that target the immune system to treat cancers; however, these drugs are mainly designed to act against late stages of cancers, when cancer cells have already spread to other parts of the body. The limited success of these drugs highlights the need for a fundamentally new approach to cancer treatment using the immune system. The goal of this application is to explore the anti-tumor properties of an immune factor called thymic stromal lymphopoietin (TSLP) that can drive a high degree of immune activation sufficient to prevent cancer formation from pre-cancerous lesions in the first place. This research raises a great opportunity to discover the immune mechanism mediating the anti-tumor effects of TSLP, which can be leveraged in cancer therapy and prevention. To pursue this goal, I will study skin cancer as an ideal cancer model in which the spatial and temporal relationship between inflammation and cancer development can be determined with exceptional precision. Moreover, skin cancer is the most common type of cancer; it is readily identifiable, and amenable to treatment. With the ultimate goal of improving cancer treatment, I plan to study the underlying mechanism of immune activation by TSLP and determine its impact on skin cancer therapy in patients. TSLP is made in the skin and plays a critical role in causing allergic diseases such as eczema. We and others have demonstrated that the skin rash caused by high TSLP levels leads to strong cancer resistance in the affected skin. Our findings are supported by population studies showing resistance to skin cancers among patients with allergic diseases. Importantly, we have found that a short-term increase in TSLP levels leads to a long-lasting resistance to skin cancer with no sign of allergic skin disease in our animal models and patients. This data provides the evidence that immune factors causing inflammatory diseases can be optimized for use in cancer therapy while avoiding their chronic side effects. To determine if TSLP is a good candidate for use in skin cancer immunotherapy, I will study how TSLP causes skin cancer resistance. Specifically, this application will apply mouse models of skin cancer and data from clinical trials to determine (1) the tumor-associated signals that are detected by TSLP-stimulated immune cells to specifically target the tumors, (2) the downstream mechanism by which TSLP-activated immune cells suppress skin cancer development, and (3) the effects of TSLP induction on pre- cancerous skin lesions in humans. The outcome of these studies will help shed light on the mechanism of TSLP action against cancer and promote its development for skin cancer immunotherapy. Considering the emerging importance of the immune system in cancer biology, the understanding of how a pro-inflammatory factor affects cancer development is highly applicable for identifying other immune factors that can be effective in cancer treatment.

? DESCRIPTION (provided by applicant): Allergic contact dermatitis (ACD) is a common skin inflammatory condition with rapidly rising prevalence among industrial nations in recent decades. Acute ACD is characterized by an intense skin rash and itching that develops at the site of exposure to contact allergens like nickel in about 20% of general population. Acute ACD is known to have tumor-suppressing effects in the skin, which has led to its use for the treatment of warts and skin cancers. However, the effects of chronic ACD on skin cancer have not been fully investigated. Implantable medical devices such as orthopedic, dental, and cardiac implants are a source of chronic ACD. These devices are being increasingly used in medical practice, which highlights the importance of research on chronic ACD to better treat this condition and prevent its associated adverse events. In a recent report, we found that chronic ACD to an orthopedic metal implant led to an invasive skin cancer in a patient. To demonstrate a causal relationship, we used the standard mouse model of contact hypersensitivity and showed that chronic application of a contact allergen to carcinogen-treated skin led to the development of aggressive skin cancers in the animals. The chronic ACD-associated inflammation was required for the skin cancer development. Importantly, we found a similar tumor-promoting inflammatory environment surrounding the skin cancer in our patient. These findings highlight a fundamental question: how does an anti-tumor immune response turn into a pro-tumor immune environment in its chronic phase? In order to address this question and determine the mechanism of tumor promotion by chronic ACD, I hypothesized that (a) skin-derived factors mediate the transition from anti-tumor skin inflammation in acute ACD to pro-tumor skin inflammation in chronic ACD, and (b) the tumor-promoting immune environment in chronic ACD is mediated by the interactions between several groups of immune cell types. To test these hypotheses, I propose to (1) determine the mechanism that mediates the transition from tumor-suppressing immune response in acute ACD to tumor- promoting immune environment in chronic ACD, and (2) Determine the mechanism of tumor promotion in chronic ACD. The outcome of this research will provide a mechanistic insight into the role of ACD in skin cancer development. Considering the role of chronic inflammation in promoting cancer development in several organs, the understanding of how chronic ACD promotes skin cancer will be highly applicable in blocking the tumor-promoting effects of chronic inflammation in the skin and other organs.

Project Summary/Abstract: Advances in cancer immunology has led to the successful use of patients' own immune cells to combat metastatic cancers. However, the therapeutic potential of the immune system in eliminating premalignant cells and preventing their progression to invasive cancers is unclear. To determine the benefit of activating the immune system to prevent cancer development and recurrence, we study the immune pathways that lead to effective immune activation against early phases of breast cancer development. Breast cancer is the most common internal cancer and second cause of cancer deaths among women in the United States. Importantly, the individuals at high risk of developing breast cancer due to underlying genetic mutations and those with premalignant lesions can be clinically identified and treated. Therefore, discovering an effective approach to activate the patients' own immune system against early breast precursor lesions may yield a lasting memory that can prevent breast cancer development and recurrence in this high-risk population. Our previous studies have demonstrated that a skin-derived immune factor called thymic stromal lymphopoietin (TSLP) suppresses the early stages of skin and breast cancer development. We have been able to extend these finding to clinics through a randomized double-blind clinical trial in which we find TSLP induction to promote a robust immune activation against skin cancer precursors and their complete clearance. In order to determine the precise mechanism of TSLP-induced immune response against early premalignant cells in the breast, and to extend our findings to other similar immune factors in high-risk patients, we aim to (1) determine the immune cells and signals that target breast premalignant cells in response to TSLP, (2) investigate the role of other immune factors released by breast cells that can induce immune response to block breast cancer development, and (3) determine the factors that are driving the immune response in the breast glands of patients with genetic mutations and utilize them for induction of an optimal immune response against early breast cancer. The outcomes of the proposed research will establish a foundation for the use of the immune system in blocking breast cancer development and provide novel therapeutic targets for breast cancer immunoprevention.

Project Summary/Abstract: Recent success in utilizing patients? own immune cells to combat metastatic cancers highlights the ability of the immune system in providing sustained remission for patients with late-stage cancers like melanoma. However, the role of the immune system in eliminating premalignant cells and preventing their progression to invasive cancers remains uncertain. To determine the benefit of activating the immune system to prevent cancer development and recurrence, we study the immune pathways that lead to effective immune activation against early phases of skin cancer development. Non-melanoma Skin cancers (NMSCs) are collectively the most commonly diagnosed cancers in the United States. cutaneous squamous cell carcinoma (SCC) is associated with severe morbidities including disfigurement, ulceration and infection, and a mortality rate similar to that of melanoma. Importantly, the SCC precursors can be clinically identified and treated. Based on compelling preclinical data, we have performed a randomized double-blind clinical trial in which we find topical calcipotriol together with 5-fluorouracil (5-FU) to promote a robust adaptive immune activation against skin cancer precursors, actinic keratoses, and their complete clearance. Importantly, this immunotherapy led to a significantly lower risk of SCC compared to 5-FU monotherapy group in 3 years post-trial. In order to determine the precise mechanism of calcipotriol plus 5-FU action against early premalignant cells in the skin, and to fully harness its potential to prevent skin cancer, we aim to (1) determine the signals that direct the immune cells to the premalignant cells treated with calcipotriol plus 5-FU combination, (2) investigate the mechanism by which these activated immune cells eliminate the targeted tumor cells, and (3) identify the immune cells and factors that mediate the long-term protective effects of calcipotriol plus 5-FU against SCC. The outcomes of the proposed research will establish a fundamental role for immune activation in combating the early stages of skin cancer development and provide the rationale for the use of calcipotriol plus 5-FU combination in skin cancer immunotherapy and immunoprevention.

Project Summary/Abstract: Research in the field of microbiome has largely focused on the beneficial effects of commensal bacteria in regulating tissue homeostasis and the immune responses. However, a commensal role for virome in supporting human health has not been explored. We propose to investigate the commensal virome and its beneficial impact on tissue homeostasis and cancer protection in barrier epithelia. Informed by our recent discovery of the beneficial role of low-risk commensal papillomaviruses and the immunity against them in protecting the skin against carcinogen-driven cancer, we propose a completely novel approach to prevent nonviral cancers by using the patients? own virome and the immune system to precisely target early malignant clones within the barrier epithelia. In particular, the widespread presence of commensal human papillomaviruses (HPVs) in barrier epithelia and the ability of a competent immune system in adults to control these viruses will provide a unique opportunity to determine the interplay of commensal viruses, epithelial tumors and the immune system. To accomplish this, we will use novel mouse models of papillomavirus colonization to (1) determine the impact of commensal HPVs on maintaining the homeostasis of epithelium exposed to environmental carcinogens, (2) identify the innate immune factors that are required for the activation of antiviral T cells targeting malignant cells while spare the virus-positive normal tissue, and (3) determine the role of papillomaviruses that colonize the oral mucosa on the carcinogen-induced head and neck cancer. The outcomes of the proposed research will establish a fundamental role for commensal virome in combating the early stages of cancer development and provide the means to prevent and treat nonviral epithelial cancers using patients? own virome and the immune cells.