Hepatology: Xu Xiao's team at Zhejiang University revealed the key mechanism of liver cancer immunotherapy failure

Hepatocellular carcinoma (HCC) is the most common primary liver tumor and one of the leading causes of cancer-related death worldwide, mainly associated with hepatitis B or C virus infection, alcoholism, and metabolic syndrome
.
Various tyrosine kinase inhibitors (TKIs) have been used as first- or second-line clinical treatments for advanced liver cancer, but their efficacy in prolonging survival is limited because the liver presents with an immunosuppressive microenvironment and is easily tolerated
to foreign factors.
On the other hand, the enrichment of tumor-associated macrophages (TAMs) and the depletion of tumor-infiltrating lymphocytes (TILs) in liver cancer promote a weakened
adaptive immune response in HCC patients.

Immune checkpoints, including CTLA-4 and PD-1, prevent overactivation
of effector lymphocytes.
The PD-1 inhibitor nivolumab has received accelerated approval from the US FDA for the treatment of patients with advanced liver cancer who have previously been treated with sorafenib
.
However, many liver cancer patients still do not benefit
from immunotherapy.
Mechanistically, failure of antigen presentation, suppressive immune microenvironment, changes in immune checkpoint molecules, and immunosuppressive cells are all potential factors for
immunotherapy failure.
Further excavation of the key events of the failure of immunotherapy for liver cancer has a great effect on improving the effect
of immunotherapy.

Recently, Professor Xiao Xu's team of Zhejiang University School of Medicine published a research paper
entitled: SULT2B1-CS-DOCK2 Axis Regulates Effector T Cell Exhaustion in Hepatocellular Carcinoma Microenvironment in Hepatology, an authoritative journal of international hepatology.

The research team discovered a lymphocyte migration-related kinase with high expression in liver cancer-infiltrating T cells: cytoplasmic division protein 2 (DOCK2)
from large samples of liver cancer proteomics data through machine learning.
It is essential
for effector T cell infiltration and anti-cancer functions.
Tumor cells with high expression of sulfotransferase 2B1 (SULT2B1) will release cholesterol sulfate, inhibit DOCK2 enzyme activity, destroy the mitochondrial homeostasis of effector T cells, promote the depletion of the function of effector T cells, allow tumor cells to gain resistance to immunotherapy, and accelerate the progression
of liver cancer.

Figure 1.
A-B, liver cancer tissue chip analysis showed the highest
proportion of DOCK2-positive CD8+T cells.
C, Reduced T cell infiltration in the DOCK2 inhibitor CPYPP-treated Hepa1-6 orthotopic transplant tumor model
.
D,CPYPP inhibits mitochondrial metabolism
in CD8+ T cells.
E,CPYPP promotes mitochondrial vacuole production
in CD8+T cells.
F, cholesterol sulfate CS reduces CD8+T cell infiltration and promotes myeloid inhibitory cell infiltration
.
G, virtual screening showing affinity ordering
of small molecules with SULT2B1.
H, molecular docking showed strong binding of THCL to SULT2B1
.

In order to weaken the resistance of liver cancer to immunotherapy, reverse the functional depletion of effector T cells in the HCC microenvironment, and restore the migration and killing ability of DOCK2-mediated effector T cells, the project team discovered some small molecule drugs, such as irinotecan (CPT-11) or torahuangurea (THCL), which can restore the killing ability of effector T cells by inhibiting the release of CS mediated by SULT2B1 and enhance the effect
of immunotherapy.

Figure 2.
Hepatoma cells highly express SULT2B1, which catalyzes the production of cholesterol sulfate, inhibits the activity of DOCK2 enzyme in tumor-infiltrating T cells, and promotes T cell depletion; Ingestion of exogenous small molecule drugs can inactivate SULT2B1 and restore the killing ability
of liver cancer-infiltrating T cells.

The corresponding authors of the paper are Professor Xu Xiao of Zhejiang University School of Medicine and Lu Di, deputy chief physician
of the Department of Hepatobiliary and Pancreatic Surgery, Hangzhou First Hospital affiliated to Zhejiang University School of Medicine.
The first author of the paper is Dr.
Wang Shuai, a distinguished associate researcher of Hangzhou First Hospital and PI of Zhejiang Key Laboratory of Cancer Fusion Research and Intelligent Medicine, and Wang Rui, a doctoral student and a master's student of Zhejiang University School of Medicine, are co-first authors
.