Distinct hepatic immunological patterns are associated with the progression or inhibition of hepatocellular carcinoma

Faridoddin Mirshahi; Hussein F Aqbi; Madison Isbell; Saeed H Manjili; Chunqing Guo; Mulugeta Saneshaw; Dipankar Bandyopadhyay; Mikhail Dozmorov; Archit Khosla; Katy Wack; Oscar M Carrasco-Zevallos; Michael O Idowu; Xiang-Yang Wang; Arun J Sanyal; Masoud H Manjili

doi:10.1016/j.celrep.2022.110454

Distinct hepatic immunological patterns are associated with the progression or inhibition of hepatocellular carcinoma

Cell Rep. 2022 Mar 1;38(9):110454. doi: 10.1016/j.celrep.2022.110454.

Authors

Affiliations

¹ Department of Internal Medicine, VCU School of Medicine, Richmond, VA 23298, USA.
² Department of Internal Medicine, VCU School of Medicine, Richmond, VA 23298, USA; VCU Massey Cancer Center, 401 College Street, Richmond, VA 23298, USA; College of Science, Mustansiriyah University, Baghdad, Iraq.
³ Department of Microbiology & Immunology, VCU School of Medicine, Richmond, VA 23298, USA.
⁴ Department of Human & Molecular Genetics, VCU School of Medicine, Richmond, VA 23298, USA.
⁵ VCU Massey Cancer Center, 401 College Street, Richmond, VA 23298, USA.
⁶ VCU Massey Cancer Center, 401 College Street, Richmond, VA 23298, USA; Department of Biostatistics, Virginia Commonwealth University, Richmond, VA 23298, USA.
⁷ PathAI, Inc., Boston, MA 02215, USA.
⁸ VCU Massey Cancer Center, 401 College Street, Richmond, VA 23298, USA; Department of Pathology, VCU School of Medicine, Richmond, VA 23298, USA.
⁹ VCU Massey Cancer Center, 401 College Street, Richmond, VA 23298, USA; Department of Human & Molecular Genetics, VCU School of Medicine, Richmond, VA 23298, USA; Hunter Holmes McGuire VA Medical Center, Richmond, VA 23298, USA.
¹⁰ Department of Internal Medicine, VCU School of Medicine, Richmond, VA 23298, USA; VCU Massey Cancer Center, 401 College Street, Richmond, VA 23298, USA. Electronic address: arun.sanyal@vcuhealth.org.
¹¹ Department of Microbiology & Immunology, VCU School of Medicine, Richmond, VA 23298, USA; VCU Massey Cancer Center, 401 College Street, Richmond, VA 23298, USA; Department of Pathology, VCU School of Medicine, Richmond, VA 23298, USA. Electronic address: masoud.manjili@vcuhealth.org.

Abstract

To discover distinct immune responses promoting or inhibiting hepatocellular carcinoma (HCC), we perform a three-dimensional analysis of the immune cells, correlating immune cell types, interactions, and changes over time in an animal model displaying gender disparity in nonalcoholic fatty liver disease (NAFLD)-associated HCC. In response to a Western diet (WD), animals mount acute and chronic patterns of inflammatory cytokines, respectively. Tumor progression in males and females is associated with a predominant CD8^{+ >} CD4⁺, Th1 > Th17 > Th2, NKT > NK, M1 > M2 pattern in the liver. A complete rescue of females from HCC is associated with an equilibrium Th1 = Th17 = Th2, NKT = NK, M1 = M2 pattern, while a partial rescue of males from HCC is associated with an equilibrium CD8⁺ = CD4⁺, NKT = NK and a semi-equilibrium Th1 = Th17 > Th2 but a sustained M1 > M2 pattern in the liver. Our data suggest that immunological pattern-recognition can explain immunobiology of HCC and guide immune modulatory interventions for the treatment of HCC in a gender-specific manner.

Keywords: DIAMOND; NASH; Th1; Th17; hepatocellular carcinoma; immunological patterns; immunotherapy; inflammation; macrophages; nonalcoholic fatty liver disease.

Publication types

Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Carcinoma, Hepatocellular* / pathology
Diet, Western
Disease Progression
Female
Liver Neoplasms* / pathology
Male
Non-alcoholic Fatty Liver Disease* / pathology

Abstract

Publication types

MeSH terms

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