CD8 T cells enhance the anti-tumor efficacy of Trametinib in head and neck cancer

Acquisition of resistance to anti-cancer therapies is associated with increase expression of immuno-suppressor modulators that enable tumor cells to escape from the anti-tumor immunity machinery. To understand the mechanisms of immune-escape from MEK inhibitor in head and neck cancer (HNC), we have developed two MAPK pathway-driven cancers in immunocompetent mice. Specifically, 4NQO (Tobacco surrogate) -carcinogenesis induced HNC model, and novel KRAS_G12-driven HNC models using CRISPR technology. Both of these HNC models are sensitive to MEK1/2 inhibitor, Trametinib, however, over time resistance was developed and tumor progression was detected. Analysis of the tumor site during the aqusition of resistance indicated that the tumor cells and the tumor ecosystem were altered. At the initial response we detected a massive infiltration of CD8 T cells, however upon progression tumor site was enriched with exhausted CD8 T cells that express high levels of PD-1. Depletion of CD8 T cells reduced Trametinib efficacy, and blocking the immune-escape mechanisms using anti PD-1/PD-L1 drugs together with Trametinib induced tumor eradication and most mice were cured. Mechanistically, we found that chronic treatment with Trametinib induces both an upregulation of PD-L1 expression by tumor cells, and an accumulation of CD11c cells that express PD-L1. Overall, our findings suggest that simultaneous administration of blockers of the PD1/PD-L1 axis may enhance the clinical activity of MAPK-targeted drugs and delay the appearance of resistance.