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Updated: Sep 13, 2025
An Oncogenic Hepatocyte-Induced Orthotopic Mouse Model of Hepatocellular Cancer Arising in the Setting of Hepatic Inflammation and Fibrosis
Published on: September 12, 2019
Neoadjuvant immune checkpoint inhibition improves protection against hepatic melanoma metastasis
Sebastian A Wohlfeil1, Céline Weller2, Bianca Dietsch2
1Department of Dermatology, Venereology, and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University, and Center of Excellence in Dermatology, Mannheim, Germany; Section of Clinical and Molecular Dermatology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Background:
Liver metastasis of cutaneous melanoma (CM) correlates with a decreased response to immune checkpoint inhibition (ICI). Here, we investigated whether neoadjuvant ICI protects against liver metastasis to prevent the development of therapy resistances.
Methods:
A stage II CM was modeled by intracutaneous injections of WT31 or B16F10 luc2 melanoma cells. Combined ICI (anti-PD-1/anti-CTLA-4) was applied in murine models of hepatic melanoma metastasis comparing neoadjuvant or adjuvant regimens. Immune cell composition and responses in the liver and CMs were comparatively analyzed by scRNA-Seq, flow cytometry, immunofluorescence, in situ hybridization and multiplex cytokine assays.
Results:
Neoadjuvant ICI resulted in improved protection against liver metastasis in comparison to adjuvant therapy. This superior response was associated with an expansion of T cells in CMs, the peripheral blood and the liver. An increased expression of TH1-associated markers and a downregulation of TH2-associated markers were detected in T cells from CMs and livers of mice by scRNA-Seq and immunofluorescence after neoadjuvant ICI. Analysis of hepatic cytokines also revealed lower levels of TH2-associated IL-4 and of IL-15.
Conclusion:
Our data demonstrate that neoadjuvant ICI provides superior protection against hepatic melanoma metastasis with a shift towards an anti-tumor TH1 immune response. Therefore, neoadjuvant ICI is a promising therapeutic option for CM to prevent the development of organ-specific therapy resistance mechanisms.
Insights
Neoadjuvant immune checkpoint inhibition (ICI) offers superior protection against liver metastasis in cutaneous melanoma (CM) by promoting an anti-tumor TH1 immune response, preventing therapy resistance.
Area of Science:
- Immunology
- Oncology
- Melanoma Research
Background:
- Cutaneous melanoma (CM) with liver metastasis shows poor response to immune checkpoint inhibition (ICI).
- Investigating neoadjuvant ICI to prevent liver metastasis and therapy resistance is crucial.
Purpose of the Study:
- To evaluate the efficacy of neoadjuvant ICI in preventing liver metastasis of CM.
- To understand the immune mechanisms underlying the protective effects of neoadjuvant ICI.
Main Methods:
- Murine models of hepatic melanoma metastasis were established using CM cells.
- Combined ICI (anti-PD-1/anti-CTLA-4) was administered in neoadjuvant and adjuvant settings.
- Immune cell composition and responses were analyzed using scRNA-Seq, flow cytometry, and cytokine assays.
Main Results:
- Neoadjuvant ICI significantly improved protection against liver metastasis compared to adjuvant therapy.
- Neoadjuvant ICI led to T cell expansion in tumors, blood, and liver, with a shift towards TH1 markers.
- Reduced TH2-associated cytokines (IL-4, IL-15) were observed in the liver after neoadjuvant ICI.
Conclusions:
- Neoadjuvant ICI provides superior protection against hepatic melanoma metastasis.
- This protection is mediated by a shift towards an anti-tumor TH1 immune response.
- Neoadjuvant ICI is a promising strategy to prevent organ-specific therapy resistance in CM.
