Neoadjuvant immune checkpoint inhibition improves protection against hepatic melanoma metastasis

Abstract

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 T_H1-associated markers and a downregulation of T_H2-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 T_H2-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 T_H1 immune response. Therefore, neoadjuvant ICI is a promising therapeutic option for CM to prevent the development of organ-specific therapy resistance mechanisms.