661 A20 determines the therapeutic effect of anti-PD-1 immunotherapy in melanoma

The therapeutic effect of immune checkpoint blockade (ICB) therapy, especially the inhibition of programmed cell death protein 1 (PD-1) and its ligand PD-L1, has been verified in melanoma treatment. However, the dissatisfied response rate and therapeutic efficacy of anti-PD-1/PD-L1 therapy remains a major challenge for melanoma treatment. Here, we reported A20 as a critical regulator that determines the therapeutic effect of anti-PD-1 immunotherapy in melanoma. Through the un-targeted MS-based proteomic analysis, we first found that high expression of A20 was significantly associated with therapeutic resistance to anti-PD-1 immunotherapy in melanoma patients. We then proved that the suppression of tumoral A20 expression potentiated the anti-tumor activity of infiltrated CD8+T cells and increased the efficacy of anti-PD-1 antibody treatment in pre-clinical mice model. A20 promoted PD-L1 expression in tumor cell to impair infiltrated CD8+T cell cytotoxicity and contributed to melanoma immune escape and therapeutic resistance to anti-PD-1 immunotherapy. Moreover, up-regulated A20 expression facilitated PD-L1 transcription via the ubiquitination and degradation of PHB and thereby ameliorating its inhibition of STAT3. Our findings reveal a previously un-recognized regulatory role of A20 in anti-tumor immunity, and demonstrate that A20 can be exploited as a promising target to overcome immune escape and improve the effect of anti-PD-1 immunotherapy in melanoma.