Inhibition of PARP14 restores response to a-PD1 immune checkpoint inhibition in tumours with resistance driven by IFN?. PARP14 study.

While immune checkpoint blockade therapy (ICBT) benefits cancer patients, many fail to maintain their response due to adaptive resistance mechanisms. IFN? is critical for cellular immunity, but also promotes adaptive resistance to ICBT. We have established a role for PARP14 in mediating IFN?-induced adaptive resistance. We confirm that chronic pre-treatment of tumour cells with IFN? confers resistance to a-PD-1 antibodies in syngeneic mouse tumour models. We identified that PARP14 was consistently upregulated in cancer cells treated chronically with IFN? as well as in IFN?-high melanoma samples. Further, we showed that PARP14 knockdown or pharmacological inhibition restores sensitivity to a-PD-1 antibodies accompanied by increased immune cell infiltration into tumours but the decreased presence of regulatory T cells. RNA sequencing analysis of tumours and cultured cells treated with PARP14 inhibitor showed an upregulation of inflammatory-related pathways. In conclusion, PARP14 is an actionable target for reversing IFN?-driven adaptive resistance to ICBT.