Immune checkpoint blockade and MAPK-targeted combined
therapy is a promising regimen for advanced
melanoma patients. However, the clinical benefit from this combo regimen remains limited, especially in patients who acquired resistance to MAPK-targeted
therapy. Here, we systematically characterized the immune landscape during MAPK-targeted
therapy in patients and mouse
melanoma models. We observed that both the abundance of
tumor-infiltrated T cells and the expression of immune-related genes were upregulated in the
drug-responsive period, but downregulated in the resistance period, implying that acquired drug resistance dampens the antitumor immune response. Further transcriptomic dissection indicated that loss of MHC-
I antigen presentation on
tumor cells plays a critical role in the reduction of T cell infiltration during drug resistance. Survival analysis demonstrates that loss of antigen presentation and reduction of T-cell infiltration during acquired drug resistance are associated with poorer clinical response and prognosis of anti-PD-1
therapy in
melanoma patients. In addition, we identified that alterations in the MAPK inhibitor resistance-related oncogenic signaling pathway closely correlated with deficiency of MHC-
I antigen presentation, including activation of the PI3K-mTOR, MAPK, and Wnt pathways. In conclusion, our research illuminates that decreased infiltration of T cells is associated with acquired drug resistance during MAPK-targeted
therapy, which may underlie the cross-resistance to
immune checkpoint blockade.