报告时间：2016年10月25日（星期二）10:00-11:00

报告地点：能源楼会议中心二号会议室（204）

报告人： Kathryn Miller-Jensen

Yale University, United States

　　报告摘要： 

    Macrophages fight infections and contribute to wound healing and tissue homeostasis. To accomplish this diverse array of functions, macrophage polarization is precisely regulated by environmental cues; however, upon acute stimulation, macrophages display significant cell-to-cell heterogeneity in transcription and secretion. These observations raise critical questions about how macrophages coordinate diverse but specific responses to environmental inputs, and how these responses become dysregulated in cancer and other diseases.

    To address these questions, my lab uses single-cell technologies to explore the consequences of macrophage functional heterogeneity in normal and tumor microenvironments. Using a microwell array functionalized with capture antibodies, we collect highly multiplexed measurements of functional secretion from hundreds of single cells, and we observe significant cell-to-cell heterogeneity in macrophage secretion in response to pro- and anti-inflammatory stimuli. By comparing single-cell measurements with in vitro cell-population data, we discovered a critical role for paracrine signaling in coordinating the cell-population response to pro-inflammatory M1 polarization by lipopolysaccharide (LPS). Network modeling of these single-cell data sets uncovered key regulatory connections between cytokines in the LPS-stimulated network. Tumor necrosis factor-α(TNF), the most highly connected cytokine in the network, exhibited highly heterogeneous secretion, such that a small fraction of cells appeared to drive the LPS response.

    We are also using single-cell secretion profiling to study tumor-associated macrophages (TAMs) isolated from murine melanoma tumors. We find TAMs isolated from untreated, late-stage tumors are largely quiescent with some M2-like, pro-tumor functions. TAM-targeted immunotherapies that slow tumor growth lead to an increase in M1-like, pro-inflammatory functions–including increased TNF secretion–in TAMs that still retain some M2-like functionality. Neutralizing TNF partly reverses treatment efficacy. Overall, our results suggest that subsets of TAMs with mixed functionality mediate the effects of TAM-targeted immunotherapies in melanoma.

    This work is funded by the NIH (U01CA164252-01), a Yale Cancer Center Collaborative Pilot Grant, and an NSF CAREER award.  

　　报告人简介： 

    Kathryn is an Assistant Professor of Biomedical Engineering at Yale. Before joining the faculty, she was an NIH Postdoctoral Fellow at UC Berkeley in the Schaffer laboratory.

    Kathryn worked previously at the National Academies, Merck Pharmaceuticals, the Chinese Academy of Sciences, and Monitor Group. She received her Ph.D. in Chemical Engineering at MIT with Doug Lauffenburger. and her B.E. & B.A. degrees at Dartmouth College.

    报告联系人：18T4组 陆瑶（9390）