Content area
Abstract
The highly variable response rates to immunotherapies underscore our limited knowledge about how tumors can manipulate immune cells. Here the membrane topology of natural killer (NK) cells from patients with liver cancer showed that intratumoral NK cells have fewer membrane protrusions compared with liver NK cells outside tumors and with peripheral NK cells. Dysregulation of these protrusions prevented intratumoral NK cells from recognizing tumor cells, from forming lytic immunological synapses and from killing tumor cells. The membranes of intratumoral NK cells have altered sphingomyelin (SM) content and dysregulated serine metabolism in tumors contributed to the decrease in SM levels of intratumoral NK cells. Inhibition of SM biosynthesis in peripheral NK cells phenocopied the disrupted membrane topology and cytotoxicity of the intratumoral NK cells. Targeting sphingomyelinase confers powerful antitumor efficacy, both as a monotherapy and as a combination therapy with checkpoint blockade.
NK cells require an immunological synapse to kill cancer cells and these synapses have been shown to have membranous protrusions. Here the authors use cutting-edge imaging and other techniques to show that tumor serine metabolism results in a reduction in NK cell sphingomyelin content and a lack of these membranous protrusions, which could contribute to a failure to kill cancer cells.
Details
; Hou, Zhuanghao 2 ; Qian, Yeben 3 ; Zhang, Yongwei 3 ; Cui, Quanwei 3 ; Wang, Xuben 4 ; Shen, Yiqing 4 ; Liu, Zhenbang 5 ; Zhou, Yonggang 4 ; Fu, Binqing 4 ; Sun, Rui 4
; Tian, Zhigang 6
; Huang, Guangming 2
; Wei, Haiming 7
1 University of Science and Technology of China, Hefei National Research Center for Physical Sciences at the Microscale, CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, Hefei, China (GRID:grid.59053.3a) (ISNI:0000000121679639); Institute of Immunology, Biomedical Sciences and Health Laboratory of Anhui Province, University of Science and Technology of China, Hefei, China (GRID:grid.59053.3a) (ISNI:0000000121679639); The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, China (GRID:grid.59053.3a) (ISNI:0000000121679639)
2 The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, China (GRID:grid.59053.3a) (ISNI:0000000121679639); University of Science and Technology of China, School of Chemistry and Materials Science and National Synchrotron Radiation Laboratory, Hefei, China (GRID:grid.59053.3a) (ISNI:0000000121679639)
3 First Affiliated Hospital of Anhui Medical University, Department of General Surgery, Hefei, China (GRID:grid.412679.f) (ISNI:0000 0004 1771 3402)
4 University of Science and Technology of China, Hefei National Research Center for Physical Sciences at the Microscale, CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, Hefei, China (GRID:grid.59053.3a) (ISNI:0000000121679639); Institute of Immunology, Biomedical Sciences and Health Laboratory of Anhui Province, University of Science and Technology of China, Hefei, China (GRID:grid.59053.3a) (ISNI:0000000121679639)
5 Core Facility Center for Life Sciences, University of Science and Technology of China, Hefei, China (GRID:grid.59053.3a) (ISNI:0000000121679639)
6 University of Science and Technology of China, Hefei National Research Center for Physical Sciences at the Microscale, CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, Hefei, China (GRID:grid.59053.3a) (ISNI:0000000121679639); Institute of Immunology, Biomedical Sciences and Health Laboratory of Anhui Province, University of Science and Technology of China, Hefei, China (GRID:grid.59053.3a) (ISNI:0000000121679639); Chinese Academy Of Medical Sciences, Research Unit Of NK Cells, Hefei, China (GRID:grid.59053.3a)
7 University of Science and Technology of China, Hefei National Research Center for Physical Sciences at the Microscale, CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, Hefei, China (GRID:grid.59053.3a) (ISNI:0000000121679639); Institute of Immunology, Biomedical Sciences and Health Laboratory of Anhui Province, University of Science and Technology of China, Hefei, China (GRID:grid.59053.3a) (ISNI:0000000121679639); The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, China (GRID:grid.59053.3a) (ISNI:0000000121679639); Chinese Academy Of Medical Sciences, Research Unit Of NK Cells, Hefei, China (GRID:grid.59053.3a)