Enhancing PD-L1 Degradation by ITCH during MAPK Inhibitor Therapy Suppresse Acquired Resistance

MAPK inhibitor (MAPKi) therapy in melanoma leads to the accumulation of tumor-surface PD-L1/ L2, which may evade antitumor immunity and accelerate acquired resistance. Here, we discover that the E3 ligase ITCH binds, ubiquitinates, and downregulates tumor-surface PD-L1/L2 in MAPKi-treated human melanoma cells, thereby promoting T-cell activation. During MAPKi therapy in viva, melanoma cell-intrinsic ITCH knockdown induced tumor-surface PD-L1, reduced intratumoral cytolytic CD8(+) T cells, and accelerated acquired resistance only in immune-competent mice. Conversely, tumor cell-intrinsic ITCH overexpression reduced MAPKi-elicited PD-L1 accumulation, augmented intratumoral cytolytic CD8(+)T cells, and suppressed acquired resistance in Braf(V600MUT), Nros(MUT), or Nf1(MUT) melanoma and Kras(MUT)-driven cancers. CD8(+) T-cell depletion and tumor cell-intrinsic PD-L1 overexpression nullified the phenotype of ITCH overexpression, thereby supporting an in vivo ITCH-PD-L1-T-cell regulatory axis. Moreover, we identify a small-molecular ITCH activator that suppresses acquired MAPKi resistance in vivo. Thus, MAPKi-induced PD-L1 accelerates resistance, and a PD-L1-degrading ITCH activator prolongs antitumor response. SIGNIFICANCE: MAPKi induces tumor cell-surface PD-L1 accumulation, which promotes immune evasion and therapy resistance. ITCH degrades PD-L1, optimizing antitumor T-cell immunity. We propose degrading tumor cell-surface PD-L1 and/or activating tumor-intrinsic ITCH as strategies to overcome MAPKi resistance.

Automated summary

MAPKi therapy induces accumulation of PD-L1 on melanoma cells, leading to immune evasion and therapy resistance. ITCH degrades PD-L1, enhancing anti-tumor T-cell immunity. Degrading tumor cell-surface PD-L1 and/or activating intrinsic ITCH may overcome MAPKi resistance.