Neoadjuvant immune checkpoint inhibition improves protection against hepatic melanoma metastasis

Liver metastasis of cutaneous melanoma (CM) correlates with a decreased response to immunecheckpoint inhibition (ICI). Here, we investigated whether neoadjuvant ICI protects againstliver metastasis to prevent the development of therapy resistances.Combined ICI (anti-PD-1/ anti-CTLA-4) was applied in murine models of hepatic melanomametastasis comparing neoadjuvant or adjuvant regimens. Immune cell composition andresponses in the liver and CMs were comparatively analyzed by scRNA-Seq, flow cytometry,immunofluorescence, in situ hybridization or multiplex cytokine assays.Neoadjuvant ICI resulted in improved protection against liver metastasis in comparison toadjuvant 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 adownregulation of TH2-associated markers were detected in T cells from CMs and livers of miceby scRNA-Seq and immunofluorescence after neoadjuvant ICI. Analysis of hepatic cytokinesalso revealed lower levels of TH2-associated IL-4 and of IL-15. In conclusion, our datademonstrate that neoadjuvant ICI provides superior protection against hepatic melanomametastasis with a shift towards an anti-tumor TH1 immune response. Therefore, neoadjuvant ICIis a promising therapeutic option for CM to prevent the development of organ-specific therapyresistance mechanisms.