【Gut】Sun Yat-sen University and Harvard Medical School reveal the immune microenvironment of primary and recurrent liver cancer and help immunotherapy

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Written by Jevin

Hepatocellular carcinoma (HCC) is the most common primary liver cancer in adults and the most common cause
of death in patients with cirrhosis.
It occurs in an environment of chronic liver inflammation and is most closely associated
with chronic viral hepatitis infection (hepatitis B or C) or exposure to activities such as alcohol or aflatoxin.
Certain disorders, such as hemochromatosis and alpha-1 antitrypsin deficiency, significantly increase the risk of
HCC.
The 5-year survival rate of hepatocellular carcinoma is only 18%, and the high recurrence rate after resection is a major obstacle to the long-term survival of
HCC.

On January 3, 2023, Kuang Ming and Qiang Zhao of Sun Yat-sen University and Dan G.
Duda of Harvard Medical School published a research paper online in the journal Gut, which described the genomic profile and TIME
of two different types of recurrent HCC through integrated "multiomics" analysis, including whole exome sequencing, RNA-seq, scRNA-seq, multiplex immunofluorescence, flow cytometry, and in vitro functional analysis.
Studies have shown that primary liver cancer has an early recurrence time, different recurrence times, and requires different immunotherapy strategies
.

https://gut.
bmj.
com/content/early/2023/01/03/gutjnl-2022-328428

Research background

 01 

Previous studies have shown that distinguishing between truly recurrent and emerging HCC by evolutionary trajectory and genomic heterogeneity may be more reliable
than clinical definition.
A recent study using single-cell RNA sequencing revealed differences in the immune ecosystem of primary tumors versus early recurrent HCCs
.
scRNA-seq enables systematic study of various cellular components and their interactions
in TIME.
However, TIME for de novo recurrent HCC has not been described
.
Therefore, the TIME individual characteristics of neonatal HCC versus truly recurrent HCC remain unknown
.
Dissecting the immune ecosystem of two HCC recurrences could provide new insights into the heterogeneity of immune evasion mechanisms between these entities and may be key to
designing specific and effective immunotherapy strategies for true and relapsed HCCs.

Research process

 02

The researchers sequenced 5' and VDJ single-cell RNA from 34 samples from 20 patients with recurrent HCC
.
Samples from two validation cohorts were performed for batch RNA sequencing, flow cytometry, multiplex immunofluorescence, and in vitro functional analysis
.

De novo versus true recurrence was determined by analyzing mutation profiles and evolutionary trajectories in paired primary and recurrent HCC samples using whole exome sequencing, some of which occurred prior to
clinical diagnosis.
The tumor immune microenvironment (TIME) of truly recurrent HCC is characterized by increased KLRB1CD8 T cell abundance with memory phenotype and low cytotoxicity
.
In contrast, they found cytotoxic and depleted CD8 T cell enrichment
in TIME of new relapsing HCCs.
Transcriptomics and interaction analysis revealed elevated GDF15 expression on HCC cells close to dendritic cells, which may have inhibited antigen presentation and suppressed antitumor immunity
in truly recurrent lesions.
In contrast, in TIME of neonatal recurrent HCCs, myeloid cells crosstalk with T cell-mediated T cell depletion and immunosuppression
.

Research significance

 03 

Taken together, this study provides a source for genomic diagnosis and immunoprofiling for
guided immunotherapy based on HCC recurrence type and specific timing.

Resources:

https://gut.
bmj.
com/content/early/2023/01/03/gutjnl-2022-328428

Note: This article is intended to introduce the progress of medical research and cannot be used as a reference
for treatment options.
If you need health guidance, please go to a regular hospital
.