Platelets control liver tumor growth through P2Y12-dependent CD40L release in NAFLD

Chi Ma; Qiong Fu; Laurence P Diggs; John C McVey; Justin McCallen; Simon Wabitsch; Benjamin Ruf; Zachary Brown; Bernd Heinrich; Qianfei Zhang; Umberto Rosato; Sophie Wang; Linda Cui; Jay A Berzofsky; David E Kleiner; Dale B Bosco; Long-Jun Wu; Chunwei Walter Lai; Yaron Rotman; Changqing Xie; Firouzeh Korangy; Tim F Greten

doi:10.1016/j.ccell.2022.08.004

Platelets control liver tumor growth through P2Y12-dependent CD40L release in NAFLD

Cancer Cell. 2022 Sep 12;40(9):986-998.e5. doi: 10.1016/j.ccell.2022.08.004. Epub 2022 Sep 1.

Authors

Chi Ma¹, Qiong Fu¹, Laurence P Diggs¹, John C McVey², Justin McCallen¹, Simon Wabitsch¹, Benjamin Ruf¹, Zachary Brown¹, Bernd Heinrich³, Qianfei Zhang¹, Umberto Rosato¹, Sophie Wang¹, Linda Cui¹, Jay A Berzofsky⁴, David E Kleiner⁵, Dale B Bosco⁶, Long-Jun Wu⁶, Chunwei Walter Lai⁷, Yaron Rotman⁷, Changqing Xie¹, Firouzeh Korangy¹, Tim F Greten⁸

Affiliations

¹ Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
² Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH 44106, USA.
³ Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; Department of Gastroenterology, Hepatology, and Endocrinology, Medical School Hannover, Hannover, Germany.
⁴ Vaccine Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
⁵ Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
⁶ Department of Neurology, Mayo Clinic, Rochester, MN, USA.
⁷ Liver and Energy Metabolism Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
⁸ Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; NCI CCR Liver Cancer Program, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: tim.greten@nih.gov.

Abstract

Platelets, the often-overlooked component of the immune system, have been shown to promote tumor growth. Non-alcoholic fatty liver disease (NAFLD) is a common disease in the Western world and rising risk for hepatocellular carcinoma (HCC). Unexpectedly, we observed that platelets can inhibit the growth of established HCC in NAFLD mice. Through pharmacological inhibition and genetic depletion of P2Y12 as well as in vivo transfusion of wild-type (WT) or CD40L^-/- platelets, we demonstrate that the anti-tumor function of platelets is mediated through P2Y12-dependent CD40L release, which leads to CD8⁺ T cell activation by the CD40 receptor. Unlike P2Y12 inhibition, blocking platelets with aspirin does not prevent platelet CD40L release nor accelerate HCC in NAFLD mice. Similar findings were observed in liver metastasis models. All together, our study reveals a complex role of platelets in tumor regulation. Anti-platelet treatment without inhibiting CD40L release could be considered for liver cancer patients with NAFLD.

Keywords: CD40L; HCC; NAFLD; P2Y12; liver metastasis; platelets.

Published by Elsevier Inc.

MeSH terms

Animals
Blood Platelets / immunology*
CD40 Ligand / genetics
Carcinoma, Hepatocellular* / genetics
Liver Neoplasms* / drug therapy
Liver Neoplasms* / genetics
Mice
Non-alcoholic Fatty Liver Disease* / drug therapy
Non-alcoholic Fatty Liver Disease* / genetics
Receptors, Purinergic P2Y12 / metabolism*

Substances

P2ry12 protein, mouse
Receptors, Purinergic P2Y12
CD40 Ligand

Abstract

MeSH terms

Substances

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