Melanoma-Associated Lymphangiogenesis, Immune Suppression, and Response to Targeted Therapy
Abstract
Amanda W. Lund, Ph.D., is a cell and tissue biologist with interdisciplinary training in tumor immunology and bioengineering. Dr. Lund brings a unique approach to understanding how the environment around the tumor communicates information to the rest of the body effectively shutting down our natural ability to remove the tumor. To complement Dr. Lund s expertise in lymphatic biology and immunology, the career development plan outlined in this proposal will focus on establishing critical competencies in melanoma biology, dermatology, and clinical translation. The richness of the Oregon Health and Science University community and the Knight Cancer Institute, the dedication of melanoma expert, Sancy Leachman, M.D., Ph.D., (designated mentor), and the support of a committee of experts spanning the interdisciplinary fields of this proposal will ensure the continual success and advancement of Dr. Lund as a professional scientist and the exposure and impact of her research program in melanoma-associated lymphangiogenesis and immune suppression. In the United States, the lifetime risk of developing malignant melanoma is 1 in 90 with a mortality rate of 1 in 400. Unlike many other cancers, the incidence in melanoma is rising, largely due to environmental factors such as intermittent, intense exposure to sunlight. While the use of sunscreens and skin coverings is an effective preventative measure against high-risk sun exposure, active military members deployed in intensely sunny locales remain at significant risk. While surgical resection of early lesions is usually curative, late-stage melanoma is usually less responsive to therapy. Consequently, the identification of biomarkers that are predictive of prognosis and resistance to therapy is critical to the clinical management of the disease in both the general and military population. To combat melanoma, cancer immunotherapy has achieved unprecedented response rates in patients with metastatic melanoma; however, a fraction of these patients remain nonresponsive to treatment and little is known about what prevents response in this subset. In this proposal, we are testing the hypothesis that lymphatic vessels (LVs) prevent effective response to an anti-tumor immune response. The body has two vascular systems; blood vessels comprise a closed loop of vessels that deliver oxygen and nutrients to our organs while LVs are a one way drainage system that prevent swelling due to fluid accumulation and transport signals from our tissues to the immune system. Lymphatic metastasis was identified as an important negative prognostic indicator over 500 years ago, but little is known about how these vessels regulate the communication between the developing melanoma and our natural defense systems. This proposal outlines the first attempt to understand the role of LVs in regulating the immune response against melanoma in mouse models and human patient samples. We will use a model of melanoma in mice that mimics human melanoma to understand the direct way in which LVs impair host defense mechanisms and validate these results in human tumors through the use of archived patient samples to evaluate the power of LVs in predicting local immune response and outcome. This work will lay the groundwork for a melanoma-specific Immunoscore that includes LV information, therefore enhancing predictive power in clinical staging and risk assessment. Development of a melanoma-specific Immunoscore and translation into use can be achieved within the next 5 years with the guidance of Sancy Leachman, M.D., Ph.D. and Bernard Fox, Ph.D. Further, demonstration that LVs are immune suppressive will suggest that they can be used to determine potential response to therapy guiding more effective clinical trial design and allowing physicians to rationally assign therapeutics to patients based upon the immunobiology of their individual tumor. Finally, we predict that in the next 10 years we will generate interv
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 29, 2016
- Source ID
- W81XWH1510348
Entities
People
- Amanda W. Lund
Organizations
- Oregon Health & Science University
- United States Army