Journal Article
. 2020 Feb; 21(3):298-308.
doi: 10.1038/s41590-019-0589-5.

CD36-mediated metabolic adaptation supports regulatory T cell survival and function in tumors

Haiping Wang 1 Fabien Franco 1 Yao-Chen Tsui 1 Xin Xie 2 Marcel P Trefny 3 Roberta Zappasodi 4 Syed Raza Mohmood 2 Juan Fernández-García 5 Chin-Hsien Tsai 1 Isabell Schulze 4 Florence Picard 1 Etienne Meylan 6 Roy Silverstein 7 Ira Goldberg 8 Sarah-Maria Fendt 5 Jedd D Wolchok 4 Taha Merghoub 4 Camilla Jandus 1 Alfred Zippelius 3 Ping-Chih Ho 9 
  • PMID: 32066953
  •     54 References
  •     108 citations


Depleting regulatory T cells (Treg cells) to counteract immunosuppressive features of the tumor microenvironment (TME) is an attractive strategy for cancer treatment; however, autoimmunity due to systemic impairment of their suppressive function limits its therapeutic potential. Elucidating approaches that specifically disrupt intratumoral Treg cells is direly needed for cancer immunotherapy. We found that CD36 was selectively upregulated in intrautumoral Treg cells as a central metabolic modulator. CD36 fine-tuned mitochondrial fitness via peroxisome proliferator-activated receptor-β signaling, programming Treg cells to adapt to a lactic acid-enriched TME. Genetic ablation of Cd36 in Treg cells suppressed tumor growth accompanied by a decrease in intratumoral Treg cells and enhancement of antitumor activity in tumor-infiltrating lymphocytes without disrupting immune homeostasis. Furthermore, CD36 targeting elicited additive antitumor responses with anti-programmed cell death protein 1 therapy. Our findings uncover the unexplored metabolic adaptation that orchestrates the survival and functions of intratumoral Treg cells, and the therapeutic potential of targeting this pathway for reprogramming the TME.

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Fatty Acid Synthesis in Prostate Cancer: Vulnerability or Epiphenomenon?
Laura A Sena, Samuel R Denmeade.
Cancer Res, 2021 Jun 20; 81(17). PMID: 34145040    Free PMC article.
BATF Regulates T Regulatory Cell Functional Specification and Fitness of Triglyceride Metabolism in Restraining Allergic Responses.
Chengxian Xu, Yongyao Fu, +9 authors, Kai Yang.
J Immunol, 2021 Apr 22; 206(9). PMID: 33879580    Free PMC article.
Regulatory T Cells in Autoimmunity and Cancer: A Duplicitous Lifestyle.
Aikaterini Hatzioannou, Athina Boumpas, +4 authors, Panayotis Verginis.
Front Immunol, 2021 Sep 21; 12. PMID: 34539668    Free PMC article.
Targeting the spectrum of immune checkpoints in prostate cancer.
Laura A Sena, Samuel R Denmeade, Emmanuel S Antonarakis.
Expert Rev Clin Pharmacol, 2021 Jul 16; 14(10). PMID: 34263692    Free PMC article.
Bad Cholesterol Uptake by CD36 in T-Cells Cripples Anti-Tumor Immune Response.
Mikhail G Kolonin.
Immunometabolism, 2021 Oct 05; 3(4). PMID: 34603769    Free PMC article.
T cell derived HIV-1 is present in the CSF in the face of suppressive antiretroviral therapy.
Gila Lustig, Sandile Cele, +15 authors, Alex Sigal.
PLoS Pathog, 2021 Sep 24; 17(9). PMID: 34555123    Free PMC article.
Tumor-induced reshuffling of lipid composition on the endoplasmic reticulum membrane sustains macrophage survival and pro-tumorigenic activity.
Giusy Di Conza, Chin-Hsien Tsai, +16 authors, Ping-Chih Ho.
Nat Immunol, 2021 Oct 24; 22(11). PMID: 34686867    Free PMC article.
Inflammaging, an Imbalanced Immune Response That Needs to Be Restored for Cancer Prevention and Treatment in the Elderly.
Juana Serrano-López, Beatriz Martín-Antonio.
Cells, 2021 Oct 24; 10(10). PMID: 34685542    Free PMC article.
A Complex Metabolic Network Confers Immunosuppressive Functions to Myeloid-Derived Suppressor Cells (MDSCs) within the Tumour Microenvironment.
Francesca Hofer, Gianna Di Sario, +3 authors, Stefano Ugel.
Cells, 2021 Oct 24; 10(10). PMID: 34685679    Free PMC article.
Metabolic regulation of T cells in the tumor microenvironment by nutrient availability and diet.
Steven Zhao, Ronal M Peralta, +2 authors, Susan M Kaech.
Semin Immunol, 2021 Sep 01; 52. PMID: 34462190    Free PMC article.
A Forgotten Corner in Cancer Immunotherapy: The Role of Lipids.
Yang Yu, Lei Gao, +9 authors, Hao Chen.
Front Oncol, 2021 Nov 02; 11. PMID: 34722305    Free PMC article.
Does Altered Cellular Metabolism Underpin the Normal Changes to the Maternal Immune System during Pregnancy?
Benjamin J Jenkins, April Rees, Nicholas Jones, Catherine A Thornton.
Immunometabolism, 2021 Nov 04; 3(4). PMID: 34729242    Free PMC article.
Contradictory roles of lipid metabolism in immune response within the tumor microenvironment.
Weina Yu, Qingyang Lei, +5 authors, Yi Zhang.
J Hematol Oncol, 2021 Nov 08; 14(1). PMID: 34742349    Free PMC article.
Gene Doping with Peroxisome-Proliferator-Activated Receptor Beta/Delta Agonists Alters Immunity but Exercise Training Mitigates the Detection of Effects in Blood Samples.
Brigitte Sibille, Isabelle Mothe-Satney, +9 authors, Anne-Sophie Rousseau.
Int J Mol Sci, 2021 Nov 14; 22(21). PMID: 34768927    Free PMC article.
Lipid metabolism in sickness and in health: Emerging regulators of lipotoxicity.
Haejin Yoon, Jillian L Shaw, Marcia C Haigis, Anna Greka.
Mol Cell, 2021 Sep 22; 81(18). PMID: 34547235    Free PMC article.
Cancer metabolism and tumor microenvironment: fostering each other?
Yiyuan Yuan, Huimin Li, +22 authors, Shi-Min Zhao.
Sci China Life Sci, 2021 Dec 01; 65(2). PMID: 34846643
Targeted Anti-Tumor Immunotherapy Using Tumor Infiltrating Cells.
Yifan Xie, Feng Xie, +7 authors, Fangfang Zhou.
Adv Sci (Weinh), 2021 Oct 19; 8(22). PMID: 34658167    Free PMC article.
Targeting Metabolism to Control Immune Responses in Cancer and Improve Checkpoint Blockade Immunotherapy.
Angèle Luby, Marie-Clotilde Alves-Guerra.
Cancers (Basel), 2021 Dec 11; 13(23). PMID: 34885023    Free PMC article.
Differential Role of PD-1 Expressed by Various Immune and Tumor Cells in the Tumor Immune Microenvironment: Expression, Function, Therapeutic Efficacy, and Resistance to Cancer Immunotherapy.
Myeong Joon Kim, Sang-Jun Ha.
Front Cell Dev Biol, 2021 Dec 14; 9. PMID: 34901012    Free PMC article.
Computational Identification of Immune- and Ferroptosis-Related LncRNA Signature for Prognosis of Hepatocellular Carcinoma.
Anmin Huang, Ting Li, Xueting Xie, Jinglin Xia.
Front Mol Biosci, 2021 Dec 14; 8. PMID: 34901153    Free PMC article.
The mitochondrial DNA constitution shaping T-cell immunity in patients with rectal cancer at high risk of metastatic progression.
P A Bousquet, S Meltzer, +10 authors, A H Ree.
Clin Transl Oncol, 2021 Dec 29; 24(6). PMID: 34961902    Free PMC article.
Diet, lipids, and antitumor immunity.
Hannah Prendeville, Lydia Lynch.
Cell Mol Immunol, 2022 Jan 06; 19(3). PMID: 34983949    Free PMC article.
Prognostic Value of an Immune-Related Gene Signature in Oral Squamous Cell Carcinoma.
Chao Zhu, Liqun Gu, +2 authors, Changyun Fang.
Front Oncol, 2022 Jan 08; 11. PMID: 34993138    Free PMC article.
Myeloid Cell-Derived Oxidized Lipids and Regulation of the Tumor Microenvironment.
Kristin C Hicks, Yulia Y Tyurina, Valerian E Kagan, Dmitry I Gabrilovich.
Cancer Res, 2021 Nov 13; 82(2). PMID: 34764204    Free PMC article.
Altered Germinal-Center Metabolism in B Cells in Autoimmunity.
Ashton K Shiraz, Eric J Panther, Christopher M Reilly.
Metabolites, 2022 Jan 21; 12(1). PMID: 35050162    Free PMC article.
Immunometabolic rewiring in tumorigenesis and anti-tumor immunotherapy.
Xin Lian, Kailin Yang, +6 authors, Shengtao Zhou.
Mol Cancer, 2022 Jan 23; 21(1). PMID: 35062950    Free PMC article.
Metagenomic analysis of the microbiome of lung adenocarcinoma with pure ground-glass opacity.
Zhenyu Zhao, Banglun Qian, +11 authors, Fenglei Yu.
Clin Transl Med, 2022 Jan 22; 12(1). PMID: 35060677    Free PMC article.
CAR-T Plus Radiotherapy: A Promising Combination for Immunosuppressive Tumors.
Vicky Mengfei Qin, Nicole M Haynes, +2 authors, Joe Jiang Zhu.
Front Immunol, 2022 Feb 01; 12. PMID: 35095911    Free PMC article.
CHI3L1 (Chitinase 3 Like 1) upregulation is associated with macrophage signatures in esophageal cancer.
Jing Huang, Zhenlin Gu, +3 authors, Wanwei Wang.
Bioengineered, 2021 Oct 07; 12(1). PMID: 34612767    Free PMC article.
Tumor microenvironment metabolites directing T cell differentiation and function.
Xia Liu, Daniel F Hoft, Guangyong Peng.
Trends Immunol, 2022 Jan 03; 43(2). PMID: 34973923    Free PMC article.
Exosomes Recovered From the Plasma of COVID-19 Patients Expose SARS-CoV-2 Spike-Derived Fragments and Contribute to the Adaptive Immune Response.
Elisa Pesce, Nicola Manfrini, +20 authors, Renata Grifantini.
Front Immunol, 2022 Feb 04; 12. PMID: 35111156    Free PMC article.
Lipid droplets: could they be involved in cancer growth and cancer-microenvironment communications?
Polina Schwartsburd.
Cancer Commun (Lond), 2022 Jan 15; 42(2). PMID: 35029069    Free PMC article.
Ligand-activated PPARδ expression promotes hepatocellular carcinoma progression by regulating the PI3K-AKT signaling pathway.
Wei Han, Nan Wang, +2 authors, Jie Lu.
J Transl Med, 2022 Feb 14; 20(1). PMID: 35151320    Free PMC article.
Metabolic adaptation of lymphocytes in immunity and disease.
Nicole M Chapman, Hongbo Chi.
Immunity, 2022 Jan 13; 55(1). PMID: 35021054    Free PMC article.
New Developments in T Cell Immunometabolism and Implications for Cancer Immunotherapy.
Nathaniel Oberholtzer, Kristen M Quinn, Paramita Chakraborty, Shikhar Mehrotra.
Cells, 2022 Feb 26; 11(4). PMID: 35203357    Free PMC article.
CD36: an emerging therapeutic target for cancer and its molecular mechanisms.
Chengwei Ruan, Yankai Meng, Hu Song.
J Cancer Res Clin Oncol, 2022 Mar 01; 148(7). PMID: 35224665
Cancer metabolism and dietary interventions.
Lin Qian, Fan Zhang, Miao Yin, Qunying Lei.
Cancer Biol Med, 2021 Dec 22;. PMID: 34931768    Free PMC article.
A decade of checkpoint blockade immunotherapy in melanoma: understanding the molecular basis for immune sensitivity and resistance.
Alexander C Huang, Roberta Zappasodi.
Nat Immunol, 2022 Mar 05; 23(5). PMID: 35241833    Free PMC article.
Prognostic impact of body mass index (BMI) in HER2+ breast cancer treated with anti-HER2 therapies: from preclinical rationale to clinical implications.
Francesca Ligorio, Luca Zambelli, +5 authors, Claudio Vernieri.
Ther Adv Med Oncol, 2022 Mar 15; 14. PMID: 35281350    Free PMC article.
Regulatory T Cells Control Effector T Cell Inflammation in Human Prediabetes.
Rui Liu, Gabriella H Pugh, +4 authors, Barbara S Nikolajczyk.
Diabetes, 2021 Nov 06; 71(2). PMID: 34737186    Free PMC article.
Functional Diversities of Regulatory T Cells in the Context of Cancer Immunotherapy.
Ran Gao, Guo-Ping Shi, Jing Wang.
Front Immunol, 2022 Apr 05; 13. PMID: 35371055    Free PMC article.
CIMT 2021: report on the 18th Annual Meeting of the Association for Cancer Immunotherapy.
Arne Billmeier, Krutika Khinvasara, +5 authors, Mustafa Diken.
Hum Vaccin Immunother, 2022 Feb 08; 18(1). PMID: 35130105    Free PMC article.
Impacts and mechanisms of metabolic reprogramming of tumor microenvironment for immunotherapy in gastric cancer.
Lin Zhao, Yuanyuan Liu, +4 authors, Jia Wang.
Cell Death Dis, 2022 Apr 22; 13(4). PMID: 35444235    Free PMC article.
Effects of Glucose Metabolism, Lipid Metabolism, and Glutamine Metabolism on Tumor Microenvironment and Clinical Implications.
Longfei Zhu, Xuanyu Zhu, Yan Wu.
Biomolecules, 2022 Apr 24; 12(4). PMID: 35454171    Free PMC article.
Metabolic Flexibility and Mechanical Efficiency in Women Over-60.
Cristina Blasco-Lafarga, Jordi Monferrer-Marín, +2 authors, Ivan Chulvi-Medrano.
Front Physiol, 2022 Apr 26; 13. PMID: 35464093    Free PMC article.
Lipid metabolism in T cell signaling and function.
Seon Ah Lim, Wei Su, Nicole M Chapman, Hongbo Chi.
Nat Chem Biol, 2022 Apr 29; 18(5). PMID: 35484263
Tumor-infiltrating T-regulatory cells adapt to altered metabolism to promote tumor-immune escape.
Tania Sarkar, Subhanki Dhar, Gaurisankar Sa.
Curr Res Immunol, 2022 May 03; 2. PMID: 35492399    Free PMC article.
Circulating Tregs Accumulate in Omental Tumors and Acquire Adipose-Resident Features.
Mingyong Liu, Dmytro Starenki, +8 authors, Selene Meza-Perez.
Cancer Immunol Res, 2022 Mar 10; 10(5). PMID: 35263766    Free PMC article.
CD36, a signaling receptor and fatty acid transporter that regulates immune cell metabolism and fate.
Yiliang Chen, Jue Zhang, Weiguo Cui, Roy L Silverstein.
J Exp Med, 2022 Apr 20; 219(6). PMID: 35438721    Free PMC article.
Multi-scale integrative analyses identify THBS2+ cancer-associated fibroblasts as a key orchestrator promoting aggressiveness in early-stage lung adenocarcinoma.
Haitang Yang, Beibei Sun, +11 authors, Feng Yao.
Theranostics, 2022 May 14; 12(7). PMID: 35547750    Free PMC article.
Neutrophil phenotypes and functions in cancer: A consensus statement.
Daniela F Quail, Borko Amulic, +22 authors, Paul Kubes.
J Exp Med, 2022 May 07; 219(6). PMID: 35522219    Free PMC article.