Conclusion
Our results substantiate a complex and plastic phenotypic interconnection between melanoma and myeloid cells in the context of T-cell immunotherapy. Type I IFN signalling in myeloid cells was identified as a key regulator of the balance between antitumor immunity and disease-promoting inflammation, thus supporting the development of novel combinatorial immunotherapies targeting this immune cell compartment.
Methods
We utilised genetic mouse models to explore the role of the type I IFN system in CD8+ T-cell immunotherapy targeting the melanocytic lineage antigen gp100.
Results
The therapeutic efficacy of adoptively transferred T cells was found to depend on a functional type I IFN system in myeloid immune cells. Compromised type I IFN signalling in myeloid immune cells did not prevent expansion, tumor infiltration or effector function of melanoma-specific Pmel-1 CD8+ T cells. However, melanomas growing in globally (Ifnar1-/-) or conditionally (Ifnar1ΔLysM) type I IFN system-deficient mice displayed increased myeloid infiltration, hypoxia and melanoma cell dedifferentiation. Mechanistically, hypoxia was found to induce dedifferentiation and loss of the gp100 target antigen in melanoma cells and type I IFN could directly inhibit the inflammatory activation of myeloid cells. Unexpectedly, the immunotherapy induced significant reduction in tumor blood vessel density and whereas host type I IFN system was not required for the vasculosculpting, it promoted vessel permeability.