CPT1A-mediated fatty acid oxidation confers cancer cell resistance to immune-mediated cytolytic killing

Author:

Liu Zheng1ORCID,Liu Wenjie1,Wang Wei2,Ma Yibao23,Wang Yufeng4,Drum David L.4ORCID,Cai Jinyang1ORCID,Blevins Hallie1,Lee Eun35,Shah Syed36ORCID,Fisher Paul B.13ORCID,Wang Xinhui4,Fang Xianjun23,Guo Chunqing13ORCID,Wang Xiang-Yang1367ORCID

Affiliation:

1. Department of Human & Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA 23298

2. Department of Biochemistry, Virginia Commonwealth University School of Medicine, Richmond, VA 23298

3. Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, VA 23298

4. Division of Gastrointestinal and Oncologic Surgery, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114

5. Department of Microbiology and Immunology, Virginia Commonwealth University School of Medicine, Richmond, VA 23298

6. Hunter Holmes McGuire VA Medical Center, Richmond, VA 23249

7. Institute of Molecular Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA 23298

Abstract

Although tumor-intrinsic fatty acid β-oxidation (FAO) is implicated in multiple aspects of tumorigenesis and progression, the impact of this metabolic pathway on cancer cell susceptibility to immunotherapy remains unknown. Here, we report that cytotoxicity of killer T cells induces activation of FAO and upregulation of carnitine palmitoyltransferase 1A (CPT1A), the rate-limiting enzyme of FAO in cancer cells. The repression of CPT1A activity or expression renders cancer cells more susceptible to destruction by cytotoxic T lymphocytes. Our mechanistic studies reveal that FAO deficiency abrogates the prosurvival signaling in cancer cells under immune cytolytic stress. Furthermore, we identify T cell–derived IFN-γ as a major factor responsible for induction of CPT1A and FAO in an AMPK-dependent manner, indicating a dynamic interplay between immune effector cells and tumor targets. While cancer growth in the absence of CPT1A remains largely unaffected, established tumors upon FAO inhibition become significantly more responsive to cellular immunotherapies including chimeric antigen receptor-engineered human T cells. Together, these findings uncover a mode of cancer resistance and immune editing that can facilitate immune escape and limit the benefits of immunotherapies.

Funder

NIH/NCI

Department of Defense

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

Cited by 10 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3