Letter to the Editor: The Hepa 1–6 may not be suitable for use in hepatocellular carcinoma models to explore responses to drug therapy

To the editor, We read with interest the study by Zabransky et al, who analyzed the immune microenvironment in a homozygous mouse model of HCC with Hep53.4, Hepa1–6, RIL-175, and TIBx.1 The authors concluded that the Hepa 1–6 model does not encapsulate the tumor immune microenvironment of the vast majority of human HCC. Among them, the authors considered that Hepa 1–6 triggered a strong immune response and that this portended potentially misleading preclinical results. However, we would like to further broaden the conclusions. Hepa 1–6 may not be suitable for use in HCC models to explore responses to drug therapy. Firstly, the SD of the subcutaneous tumor model of the Hepa1–6 model in the article was very large in the control group, which to some extent, indicates the instability of this model. Furthermore, there was no difference in survival between the control and treatment groups in the Hepa 1–6 model, potentially suggesting that the Hepa 1–6 tumors had dissipated during development. The hematoxylin-eosin staining results in the article, as well as the immunohistochemistry results for CD8 and B220, show that Hepa 1–6 tumors are characterized by many inflammatory cells surrounding the tumor tissue, as if an army were stationed around the tumor. This is despite the relevant publications reporting solutions for this possible situation. Yang et al used younger weekly mice (4 weeks old) for Hepa 1–6 modeling.2 Some of the researchers eliminated the effect of too large SD in the control group by increasing the sample size or using tumor response rate.3,4 Even though this approach may be able to reflect differences in response to drug therapy, it is more important to use a more stable HCC model to explore responses to drug therapy.