PMID- 37722058 OWN - NLM STAT- MEDLINE DCOM- 20230928 LR - 20240319 IS - 1091-6490 (Electronic) IS - 0027-8424 (Print) IS - 0027-8424 (Linking) VI - 120 IP - 39 DP - 2023 Sep 26 TI - CPT1A-mediated fatty acid oxidation confers cancer cell resistance to immune-mediated cytolytic killing. PG - e2302878120 LID - 10.1073/pnas.2302878120 [doi] LID - e2302878120 AB - Although tumor-intrinsic fatty acid beta-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-gamma 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. FAU - Liu, Zheng AU - Liu Z AUID- ORCID: 0000-0002-7260-209X AD - Department of Human & Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA 23298. FAU - Liu, Wenjie AU - Liu W AD - Department of Human & Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA 23298. FAU - Wang, Wei AU - Wang W AD - Department of Biochemistry, Virginia Commonwealth University School of Medicine, Richmond, VA 23298. FAU - Ma, Yibao AU - Ma Y AD - Department of Biochemistry, Virginia Commonwealth University School of Medicine, Richmond, VA 23298. AD - Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, VA 23298. FAU - Wang, Yufeng AU - Wang Y AD - Division of Gastrointestinal and Oncologic Surgery, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114. FAU - Drum, David L AU - Drum DL AUID- ORCID: 0009-0005-0845-4167 AD - Division of Gastrointestinal and Oncologic Surgery, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114. FAU - Cai, Jinyang AU - Cai J AUID- ORCID: 0000-0002-7385-8281 AD - Department of Human & Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA 23298. FAU - Blevins, Hallie AU - Blevins H AD - Department of Human & Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA 23298. FAU - Lee, Eun AU - Lee E AD - Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, VA 23298. AD - Department of Microbiology and Immunology, Virginia Commonwealth University School of Medicine, Richmond, VA 23298. FAU - Shah, Syed AU - Shah S AUID- ORCID: 0009-0003-4083-0535 AD - Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, VA 23298. AD - Hunter Holmes McGuire VA Medical Center, Richmond, VA 23249. FAU - Fisher, Paul B AU - Fisher PB AUID- ORCID: 0000-0002-0085-4546 AD - Department of Human & Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA 23298. AD - Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, VA 23298. FAU - Wang, Xinhui AU - Wang X AD - Division of Gastrointestinal and Oncologic Surgery, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114. FAU - Fang, Xianjun AU - Fang X AD - Department of Biochemistry, Virginia Commonwealth University School of Medicine, Richmond, VA 23298. AD - Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, VA 23298. FAU - Guo, Chunqing AU - Guo C AUID- ORCID: 0000-0002-3148-8542 AD - Department of Human & Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA 23298. AD - Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, VA 23298. FAU - Wang, Xiang-Yang AU - Wang XY AUID- ORCID: 0000-0003-2421-5367 AD - Department of Human & Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA 23298. AD - Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, VA 23298. AD - Hunter Holmes McGuire VA Medical Center, Richmond, VA 23249. AD - Institute of Molecular Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA 23298. LA - eng GR - R01 CA259599/CA/NCI NIH HHS/United States GR - R01 CA229812/CA/NCI NIH HHS/United States GR - R01 CA226981/CA/NCI NIH HHS/United States GR - R01 CA240004/CA/NCI NIH HHS/United States GR - R01 CA175033/CA/NCI NIH HHS/United States GR - P30 CA016059/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20230918 PL - United States TA - Proc Natl Acad Sci U S A JT - Proceedings of the National Academy of Sciences of the United States of America JID - 7505876 RN - EC 2.3.1.21 (Carnitine O-Palmitoyltransferase) RN - 0 (Fatty Acids) RN - EC 2.3.1.21 (CPT1A protein, human) SB - IM MH - Humans MH - *Carnitine O-Palmitoyltransferase/genetics MH - Cytotoxicity, Immunologic MH - Fatty Acids MH - Lipid Metabolism MH - *Neoplasms/therapy MH - T-Lymphocytes, Cytotoxic PMC - PMC10523454 OTO - NOTNLM OT - cancer metabolism OT - carnitine palmitoyltransferase 1A OT - cellular immunotherapy OT - fatty acid oxidation OT - therapeutic resistance COIS- The authors declare no competing interest. EDAT- 2023/09/18 18:43 MHDA- 2023/09/20 06:42 PMCR- 2024/03/18 CRDT- 2023/09/18 15:36 PHST- 2023/09/20 06:42 [medline] PHST- 2023/09/18 18:43 [pubmed] PHST- 2023/09/18 15:36 [entrez] PHST- 2024/03/18 00:00 [pmc-release] AID - 202302878 [pii] AID - 10.1073/pnas.2302878120 [doi] PST - ppublish SO - Proc Natl Acad Sci U S A. 2023 Sep 26;120(39):e2302878120. doi: 10.1073/pnas.2302878120. Epub 2023 Sep 18.