RORc-expressing immune cells negatively regulate tertiary lymphoid structure formation and support their...

Area of Science:

• Immunology
• Oncology
• Hepatology

Background:

• RORc-expressing immune cells are crucial in inflammation, autoimmunity, and cancer.
• Tertiary lymphoid structures (TLSs) in liver cancer can be pro-tumorigenic, but their development is poorly understood.
• This study investigates RORc-expressing cells' role in TLS development within inflammation-associated liver cancer.

Purpose of the Study:

• To explore the role of RORc-expressing cells in TLS development in liver cancer.
• To determine how RORc influences the pro- or anti-tumorigenic functions of TLSs.
• To identify potential therapeutic targets for manipulating TLSs in liver cancer.

Main Methods:

• Crossed IKKβ(EE)^Hep mice with RORc knockout mice to study RORc's effect on liver inflammation, TLS, and cancer.
• Analyzed TLS phenotypes using transcriptional, proteomic, and immunohistochemical methods.
• Utilized CD4, CD8, and B-cell depletions to assess their contribution to liver TLS and tumor formation.

Main Results:

• RORc-expressing cells were found in TLSs of human and mouse intrahepatic cholangiocarcinoma.
• Absence of RORc-expressing cells led to increased TLS formation and acquisition of anti-tumorigenic properties, reducing tumor load.
• CD4 cells are essential for liver TLS formation; B cells are crucial for TLS formation specifically when RORc-expressing cells are absent.
• Anti-tumorigenic TLSs showed enrichment of exhausted CD8 cells, germinal center B cells, and plasma cells, with B cells potentially limiting tumor development via antibodies.

Conclusions:

• RORc-expressing cells negatively regulate B-cell responses and promote pro-tumorigenic functions of hepatic TLSs.
• RORc-expressing cells are key modulators of the liver immune microenvironment in cancer.
• Targeting RORc may offer a strategy to enhance anti-tumor immunity and improve outcomes in liver cancer.