Date(s) - 03/16/2015
Currently, lung cancer is the leading cause of cancer-related death in the United States, due in part to the failure of protective immunity against malignant cells. Natural Killer (NK) cells constitute nearly 10% of resident lymphocytes in the lungs, making lungs the most NK-rich non-lymphoid tissue. NK cells are poised to kill neoplastic cells; however, tumor cells evade NK cell surveillance by creating an immunosuppressive environment. We found that transforming growth factor β-1 (TGFβ) produced by tumor cells can suppress NK cell function by inducing miR-183, which binds and represses the activating adaptor protein, DAP12. By targeting DAP12, miR-183 efficiently silences NK cells by depleting the stimulatory signaling capacity necessary for lysis through associated receptors. We verified that DAP12 downregulation occurs in lung cancer patients, as tumor-infiltrating NK cells consistently expressed lower DAP12 levels than peritumoral NK cells across all known lung cancer subtypes. Because DAP12 is the common adaptor for many NK cell activating receptors, this novel miR-183-dependent pathway drives pan NK cell immunosuppression in the TGFβ-rich tumor microenvironment.
Dr. Julie Djeu received her Ph.D. in Medical Microbiology and Immunology from George Washington University in 1973 and has made an impact in unraveling the immune mechanisms against cancer that are applicable in the clinic. She is one of the pioneers in the discovery of natural killer (NK) cells and their activation by interferon, and has had a long successful career in analysis of cytokines and signal pathways that drive NK lytic function against tumor cells. She conducted her graduate work at the National Cancer Institute (NCI) where she discovered NK cells and continued to work there until she was recruited to Food and Drug Administration, Center of Biologics Evaluation and Research (FDA-CBER) in 1978 to head the cytokine biology section. In 1984, she joined the Department of Medical Microbiology and Immunology in the University of South Florida and, based on her outstanding research in cancer immunity, she was recruited to the fledging Moffitt Cancer Center in 1992 to help create a NCI-designated Cancer Center. She was the founding leader of the Immunology Program at Moffitt Cancer Center and built it into one of the premier research programs in the US that has a national and international reputation for molecular analysis of cancer immunity and transformation of these seminal discoveries into cancer immunotherapeutics. In 2013, she became the Associate Cancer Center Director for Education and Training and has been committed to establishing Moffitt Cancer Center as an educational and training center. She is on the editorial board of Cancer Research, Molecular Cancer Research, and Cancer Immunology and Immunotherapy.
Her work continues to focus on NK cells and she has made major contributions to the understanding of NK receptors and their adaptors, with emphasis on the molecular basis for NK dysfunction in the tumor microenvironment, including microRNAs. In addition to unraveling the cytokines and signal molecules that drive NK function, she has investigated monocyte and T cell responses in normal and cancer patients in depth. She has recently been analyzing the effect of chemotherapeutic agents on Th1 vs Th2 and M1 vs M2 immune responses against cancer in mouse models, in order to find novel chemoimmunomodulatory strategies to restore adaptive immunity against cancer.