Viral liver cancer vs non-viral liver cancer: Can PD-1 therapy be a one-size-fits-all approach?

By Arale

Primary liver cancer is one of the common malignant tumors.

Image from: cancer today

Statistics show that more than half of HCC is caused by HBV infection, followed by HCV

With the improvement of people's living standards, the incidence of NAFLD, which is closely related to heredity-environment-diet, is increasing year by year

Domestic and foreign liver cancer guidelines, including the NCCN Guidelines for Liver Cancer and the Guidelines for the Diagnosis and Treatment of Primary Liver Cancer (2022 Edition), all recommend PD-1/PD-L1 inhibitors (atezolizumab, sintilimab, etc.

However, in the face of different etiologies of liver cancer, is the treatment plan the same? Scientists realized that different etiologies may have different tumor biology and immune microenvironment characteristics

Nature: The impact of NASH on immunotherapy [3]

In March 2021, the top journal "Nature" published a study in which scientists used a choline-deficient high-fat diet (CD-HFD) to prepare an animal model of NASH

Number of CD8+ T cells.

Prophylactic administration of PD-1 inhibitors resulted in an increase in the incidence of NASH-HCC, the number and size of tumor nodules (bottom panel), which correlated with the number of CD8+PD1+CXCR6+, TOX+, and TNF+ T cells in the liver increase about

Note: CXCR6, a chemokine receptor, plays a key role in T cell-mediated tumor immune responses; TOX, a key regulator of tumor-specific T cell differentiation; TNF, tumor necrosis factor , is an important cytokine in the process of effector T cells killing target cells

Here is a little extension, the "T cell exhaustion" theory is an important mechanism of tumor immune escape, which originated from a mouse model of chronic viral infection

Back to this study in Nature

The results showed that immunotherapy improved the overall survival rate (HR=0.

In two additional cohorts (bottom panel), patients with NAFLD-HCC treated with PD-1/PD-L1 inhibitors had reduced overall survival compared with patients with other etiologies

NEJM: Emphasis on stratification of HCC etiology [4]

After the above study was published, it caused discussion in the field, and the top journal "New England Journal of Medicine" published a review article in July 2021

According to the article, the study in Nature raises new key questions

Although there are still many unanswered questions, this study is seminal and suggests the need for stratification by etiology in HCC clinical trials and stricter definitions of viral status, NASH, and NAFLD

According to the authors, it is too early to change the clinical practice of advanced HCC based on the Nature study
.
Atezolizumab combined with bevacizumab improves OS.
The meta-analysis has its limitations.
The meta-analysis results did not show that the survival of NASH-HCC patients was impaired, so PD-1/PD-L1 is still supported at present.
Inhibitors are used as first-line therapy
.
However, as immunotherapy progresses towards the early stages of HCC, the observations in this study need to be treated with caution and the design of subsequent clinical studies should be refined to understand the complex relationship between cancer and immune responses
.

references

1.
Guidelines for the diagnosis and treatment of primary liver cancer (2022 edition)

2.
Huang Wei, et al.
Chinese Journal of Hepatology.
2017; 25(2): 157-160.

3.
Nature.
2021; 592(7854): 450-456.

4.
N Engl J Med.
2021; 385(3): 280-282.