NAFLD indirectly impairs antigen-specific CD8+ T cell immunity against liver cancer in mice

John C McVey; Benjamin L Green; Benjamin Ruf; Justin D McCallen; Simon Wabitsch; Varun Subramanyam; Laurence P Diggs; Bernd Heinrich; Tim F Greten; Chi Ma

doi:10.1016/j.isci.2022.103847

NAFLD indirectly impairs antigen-specific CD8⁺ T cell immunity against liver cancer in mice

iScience. 2022 Feb 1;25(2):103847. doi: 10.1016/j.isci.2022.103847. eCollection 2022 Feb 18.

Authors

John C McVey^{1

2}, Benjamin L Green^{1

3}, Benjamin Ruf¹, Justin D McCallen^{1

4}, Simon Wabitsch¹, Varun Subramanyam¹, Laurence P Diggs^{1

5}, Bernd Heinrich^{1

6}, Tim F Greten^{1

7}, Chi Ma¹

Affiliations

¹ Gastrointestinal and Thoracic Malignancy Section, National Cancer Institute, National Institutes of Health, TGMB NIH/NCI/CCR Building 10 Rm 3B44 9000 Rockville Pike, Bethesda, MD, USA.
² Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
³ Surgical Oncology Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
⁴ Brody School of Medicine, East Carolina University, Greenville, NC, USA.
⁵ Department of Surgery, Rutgers New Jersey Medical School, Newark, NJ, USA.
⁶ Department of Medicine, Hannover Medical School, Hannover, Germany.
⁷ NCI CCR Liver Cancer Program, National Institutes of Health, Bethesda, MD, USA.

Abstract

Non-alcoholic fatty liver disease (NAFLD) has become an important etiology leading to liver cancer. NAFLD alters adaptive T cell immunity and has a profound influence on liver cancer development. However, it is unclear how NAFLD affects tumor antigen-specific T cell response. In this study, we generated a doxycycline-inducible MHC-I and -II antigen-expressing HCC cell line which allowed us to investigate tumor antigen-specific T cell response in two NAFLD mouse models. The system proved to be an effective and efficient way to study tumor antigen-specific T cells. Using this model, it was found that NAFLD impairs antigen-specific CD8⁺ T cell immunity against HCC. The effect was not due to reduced generation or intrinsic functional changes of tumor antigen-specific CD8⁺ T cells but caused by accumulated macrophages in the liver environment. The findings suggest that targeting macrophages in NAFLD-driven HCC may improve therapeutic outcomes.

Keywords: Cancer; Immunology.