Macrophage xCT deficiency drives immune activation and boosts responses to immune checkpoint blockade in lung cancer

Bufu Tang; Yajie Wang; Wangting Xu; Jinyu Zhu; Qiaoyou Weng; Weiqian Chen; Shiji Fang; Yang Yang; Rongfang Qiu; Minjiang Chen; Weiyang Mao; Min Xu; Zhongwei Zhao; Songhua Cai; Hongbing Zhang; Jiansong Ji

doi:10.1016/j.canlet.2022.216021

Macrophage xCT deficiency drives immune activation and boosts responses to immune checkpoint blockade in lung cancer

Cancer Lett. 2023 Feb 1:554:216021. doi: 10.1016/j.canlet.2022.216021. Epub 2022 Nov 29.

Authors

Bufu Tang¹, Yajie Wang¹, Wangting Xu², Jinyu Zhu¹, Qiaoyou Weng¹, Weiqian Chen¹, Shiji Fang¹, Yang Yang¹, Rongfang Qiu¹, Minjiang Chen¹, Weiyang Mao¹, Min Xu¹, Zhongwei Zhao¹, Songhua Cai³, Hongbing Zhang⁴, Jiansong Ji⁵

Affiliations

¹ Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital, School of Medicine, Zhejiang University, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, China.
² Department of Respiratory, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
³ Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China. Electronic address: caisonghua@chcamssz.ac.cn.
⁴ State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences and School of Basic Medicine, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China. Electronic address: hbzhang@ibms.pumc.edu.cn.
⁵ Key Laboratory of Imaging Diagnosis and Minimally Invasive Intervention Research, Lishui Hospital, School of Medicine, Zhejiang University, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, China. Electronic address: jijiansong@zju.edu.cn.

PMID: 36455758
DOI: 10.1016/j.canlet.2022.216021

Abstract

Tumor-associated macrophages (TAMs) play an important role in remodeling the tumor microenvironment (TME), which promotes tumor growth, immunosuppression and angiogenesis. Because of the high plasticity of macrophages and the extremely complex tumor microenvironment, the mechanism of TAMs in cancer progression is still largely unknown. In this study, we found that xCT (SLC7A11) was overexpressed in lung cancer-associated macrophages. Higher xCT in TAMs was associated with poor prognosis and was an independent predictive factor in lung cancer. In addition, lung cancer growth and progression was inhibited in xCT knockout mice, especially macrophage-specific xCT knockout mice. We also found that the deletion of macrophage xCT inhibited AKT/STAT6 signaling activation and reduced M2-type polarization of TAMs. Macrophage xCT deletion recruited more CD8⁺ T cells and activated the lung cancer cell-mediated and IFN-γ-induced JAK/STAT1 axis and increased the expression of its target genes, including CXCL10 and CD274. The combination of macrophage xCT deletion and anti-PDL1 antibody achieved better tumor inhibition. Finally, combining the xCT inhibitor erastin with an anti-PDL1 antibody was more potent in inhibiting lung cancer progression. Therefore, suppression of xCT may overcome resistance to cancer immunotherapy.

Keywords: Anti-tumor immunity; PDL-1; STATs; System xc(−); TAMs.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
CD8-Positive T-Lymphocytes / metabolism
Immune Checkpoint Inhibitors* / metabolism
Immune Checkpoint Inhibitors* / pharmacology
Immune Checkpoint Inhibitors* / therapeutic use
Lung Neoplasms* / drug therapy
Lung Neoplasms* / genetics
Lung Neoplasms* / metabolism
Macrophage Activation
Macrophages / metabolism
Mice
Mice, Knockout
Tumor Microenvironment

Substances

Immune Checkpoint Inhibitors