Study discovers negative regulator of natural killer cell maturation

COLUMBUS, Ohio - A new study has identified a regulatory pathway in natural killer cells that inhibits their maturation and homing behavior. Natural killer cells are one of the body's first lines of defense against viruses and cancer. The findings could lead to new strategies for boosting natural-killer cell activity against cancer and viral infections. The study was led by researchers at The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC - James). It showed that a protein called Foxo1 inhibits natural killer (NK) cell development and function. It also shows that Foxo1 exerts its inhibitory effects by blocking transcription of the gene that encodes Tbx21, which is a known positive regulator of NK-cell development and function. The research was reported in the journal Immunity. "We discovered a pathway that cancer cells may use to block NK-cell function and evade immune responses," says principal investigator Jianhua Yu, PhD, assistant professor of medicine and a member of the OSUCCC - James Leukemia Research Program. "The findings may provide us an opportunity to enhance NK-cell antitumor activity," he adds.

Yu and his colleagues used an animal model and human NK cells for the study. Key technical findings include: Foxo1 and Foxo3 control NK-cell maturation, but Foxo1 plays the major role; Reducing Foxo1 expression enhances NK-cell maturation; Foxo1 suppression of Tbx21 expression involves different mechanisms in human and mouse NK cells.

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Funding from the National Institutes of Health (CA155521, OD018403, CA095426, CA163205, CA068458, and CA185301), the National Blood Foundation, the American Cancer Society, Gabrielle's Angel Foundation for Cancer Research, the Natural Science Foundation of China, the European Research Council and the Ligue Nationale contre le Cancer (Equipe Labellisée). Other researchers involved in this study were Youcai Deng, Jianhong Chu, Shunzong Yuan, Youwei Wang, Xilin Chen, Hsiaoyin Mao, Lingling Zhang, Jianying Zhang, Tiffany Hughes, Xianghong Zou, Aharon G. Freud and Michael A Caligiuri, The Ohio State University; Yafei Deng, Qi Zhang, Fangjie Wang and Xiaohui Li, Third Military Medical University, Chongqing, China; Yann Kerdiles and Eric Vivier, Aix-Marseille University, Marseille, France; and Chang-Gong Liu, The University of Texas MD Anderson Cancer Center. The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute strives to create a cancer-free world by integrating scientific research with excellence in education and patient-centered care, a strategy that leads to better methods of prevention, detection and treatment. Ohio State is one of only 41 National Cancer Institute (NCI)-designated Comprehensive Cancer Centers and one of only four centers funded by the NCI to conduct both phase I and phase II clinical trials. The NCI recently rated Ohio State's cancer program as "exceptional," the highest rating given by NCI survey teams. As the cancer program's 306-bed adult patient-care component, The James is a "Top Hospital" as named by the Leapfrog Group and one of the top cancer hospitals in the nation as ranked by U.S.News & World Report.