Adoptive T Cell Therapy Targeting Different Gene Products Reveals Diverse and Context-Dependent Immune Evasion in Melanoma

Tumor immune escape limits durable responses to T cell therapy. Here, we examined how regulation and function of gene products that provide the target epitopes for CD8+ T cell anti-tumor immunity influence therapeutic efficacy and resistance. We used a CRISPR-Cas9-based method (CRISPitope) in syngeneic melanoma models to fuse the same model CD8+ T cell epitope to the C-termini of different endogenous gene products. Targeting melanosomal proteins or oncogenic CDK4R24C (Cyclin-dependent kinase 4) by adoptive cell transfer (ACT) of the same epitope-specific CD8+ T cells revealed diverse genetic and non-genetic immune escape mechanisms. ACT directed against melanosomal proteins, but not CDK4R24C, promoted melanoma dedifferentiation, and increased myeloid cell infiltration. CDK4R24C antigen persistence was associated with an interferon-high and T-cell-rich tumor microenvironment, allowing for immune checkpoint inhibition as salvage therapy. Thus, the choice of target antigen determines the phenotype and immune contexture of recurrent melanomas, with implications to the design of cancer immunotherapies. [Display omitted] •Comparison of different endogenous target antigens for adoptive T cell therapy•Melanoma immune escape phenotype determined by class and level of target antigen•Targeting melanosomal antigens drives dedifferentiation and myeloid infiltration•Persistence of oncogenic antigen allows for salvage immune checkpoint therapy Using mouse models of melanoma, Effern et al. demonstrate how the choice of target antigens for adoptive T cell therapy determines resistance mechanisms. Targeting melanosomal antigens promotes decreased antigen expression through melanoma dedifferentiation with myeloid cell infiltration, whereas targeting oncogenic CDK4R24C results in antigen persistence, allowing for salvage immune checkpoint therapy.