Melanoma differentiation trajectories determine sensitivity towards pre-existing CD8 + tumor-infiltrating lymphocytes

The highly plastic nature of melanoma enables its transition among diverse cell states to survive hostile conditions. However, the interplay between specific tumor cell states and intratumoral T cells remains poorly defined. With MAPKi-treated BRAF -mutant tumors as models, we linked human melanoma state transition to CD8 T cell responses. Repeatedly we observed that isogenic melanoma cells could evolve along distinct differentiation trajectories upon single BRAF inhibitor (BRAFi) or dual BRAFi/MEKi treatment, resulting in BRAFi-induced hyperdifferentiated and BRAFi/MEKi-induced dedifferentiated resistant subtypes. Taking advantage of patient-derived autologous CD8 tumor infiltrating lymphocytes (TILs), we demonstrate that progressive melanoma cell state transition profoundly affects TIL function. Tumor cells along the hyperdifferentiation-trajectory continuously gained sensitivity towards tumor-reactive CD8 TILs, while those in the dedifferentiation-trajectory acquired T cell resistance, in part due to the loss of differentiation antigens. Overall, our data reveals the tight connection of MAPKi-induced temporary (drug-tolerant transition state) and stable (resistant state) phenotype alterations with T cell function and further broadens current knowledge on melanoma plasticity in terms of sculpting local anti-tumor immune responses, with implications for guiding the optimal combination of targeted therapy and immunotherapy.