Tumors evade immune cytotoxicity by altering the surface topology of NK cells

Nat Immunol. 2023 Mar 23. doi: 10.1038/s41590-023-01462-9.

Xiaohu Zheng ^# ¹ ² ³, Zhuanghao Hou ^# ⁴ ⁵, Yeben Qian ⁶, Yongwei Zhang ⁶, Quanwei Cui ⁶, Xuben Wang ⁷ ⁸, Yiqing Shen ⁷ ⁸, Zhenbang Liu ⁹, Yonggang Zhou ⁷ ⁸, Binqing Fu ⁷ ⁸, Rui Sun ⁷ ⁸, Zhigang Tian ¹⁰ ¹¹ ¹², Guangming Huang ¹³ ¹⁴, Haiming Wei ¹⁵ ¹⁶ ¹⁷ ¹⁸

Affiliations

1 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, University of Science and Technology of China, Hefei, China. [email protected].
2 Institute of Immunology, Biomedical Sciences and Health Laboratory of Anhui Province, University of Science and Technology of China, Hefei, China. [email protected].
3 The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, China. [email protected].
4 The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, China.
5 School of Chemistry and Materials Science and National Synchrotron Radiation Laboratory, University of Science and Technology of China, Hefei, China.
6 Department of General Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, China.
7 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, University of Science and Technology of China, Hefei, China.
8 Institute of Immunology, Biomedical Sciences and Health Laboratory of Anhui Province, University of Science and Technology of China, Hefei, China.
9 Core Facility Center for Life Sciences, University of Science and Technology of China, Hefei, China.
10 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, University of Science and Technology of China, Hefei, China. [email protected].
11 Institute of Immunology, Biomedical Sciences and Health Laboratory of Anhui Province, University of Science and Technology of China, Hefei, China. [email protected].
12 Research Unit Of NK Cells, Chinese Academy Of Medical Sciences, Hefei, China. [email protected].
13 The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, China. [email protected].
14 School of Chemistry and Materials Science and National Synchrotron Radiation Laboratory, University of Science and Technology of China, Hefei, China. [email protected].
15 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, University of Science and Technology of China, Hefei, China. [email protected].
16 Institute of Immunology, Biomedical Sciences and Health Laboratory of Anhui Province, University of Science and Technology of China, Hefei, China. [email protected].
17 The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, China. [email protected].
18 Research Unit Of NK Cells, Chinese Academy Of Medical Sciences, Hefei, China. [email protected].
# Contributed equally.

PMID: 36959292 DOI: 10.1038/s41590-023-01462-9

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.

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