SOCS proteins as inhibitors of immune surveillance in the melanoma microenvironme

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DESCRIPTION (provided by applicant): This proposal is meant to assist Dr. Lesinski in his transition to becoming an independent investigator in human cancer research. Dr. Lesinski joined the Department of Molecular Virology, Immunology and Medical Genetics at The Ohio State University as an Assistant Professor on the Research Track in 2005. This three year proposal consists of a Career Development Plan designed to further enhance his ability to conduct cancer research in collaboration with clinicians. Dr. Lesinski will continue his education through involvement in various educational seminars, workshops and participation in national scientific meetings. Importantly, he will gain extensive training in the responsible conduct of clinical research, and will complete the didactic requirements to obtain a formal Master of Public Health in Clinical Investigation. Included in this proposal is a Research Plan that extends Dr. Lesinski's prior experience in immunology and oncology into novel studies that investigate how the immune system can mediate cancer control in the setting of malignant melanoma. Specifically, Dr. Lesinski will study how immunosuppressive cytokines act to inhibit the ability of immune cells to control the development of melanoma. It has previously been established that a separate group of immunostimulatory cytokines (e.g., the interferons) are critical for cancer immunosurveillance by host immune cells. The action of interferons can be negatively regulated by a group of proteins termed the "Suppressors of Cytokine Signaling" or SOCS proteins. It is hypothesized that cytokines present in the tumor microenvironment function by upregulating SOCS proteins within immune cells, making them less responsive to the cytokines that mediate immunosurveillance. Dr. Lesinski will utilize lymph node biopsies from melanoma patients to determine whether the immunosuppressive cytokines present in the tumor microenvironment lead to increased expression of SOCS proteins within immune cells, and inhibit their ability to control the development of malignant melanoma. This research is novel because it will allow for new strategies to harness the full potential of the immune system against early-stage cancer. Thus, effectively turning the immune system against micrometastatic disease is relevant to public health because it represents a promising means of reducing cancer incidence, mortality and morbidity. The data obtained from these initial studies will be used to prepare an R01 grant application focused on mechanisms of immune-mediated cancer control within two years of the K22 award. The Ohio State University's NCI designated Comprehensive Cancer Center (OSU CCC) provides the ideal location for this training. The institution is committed towards the development of Dr. Lesinski, and fully supports his decision to devote 75% of his time towards this goal.