Genetic aberrations in the CDK4 pathway are associated with innate resistance to PD-1 blockade in Chinese patients with non-cutaneous melanoma

Purpose: PD-1 checkpoint blockade immunotherapy induces long and durable response in patients with advanced melanoma. However, only a subset of melanoma patients benefit from this approach. The mechanism triggering resistance of anti-PD-1 therapy remains unclear. Experimental Design: Whole-exome sequencing (WES) and RNA sequencing (RNA-Seq) analyses were performed in a training cohort (n=31) using baseline tumor biopsies of patients with advanced melanoma treated with the anti-PD-1 antibody. Copy number variations (CNV) for the genes CDK4, CCND1 and CDKN2A were assayed using a TaqMan Copy Number Assay in a validation cohort (n=85). The effect of CDK4/6 inhibitors combined with anti-PD-1 antibody monotherapy was evaluated in PD-1 humanized mouse (C57BL/6-hPD-1) and humanized immune system (HIS) patient-derived xenograft (PDX) models. Results: WES revealed several significant gene copy number gains in the patients of no clinical benefit cohort, such as 12q14.1 loci, which harbor CDK4. The association between CDK4 gain and innate resistance to anti-PD-1 therapy was validated in 85 melanoma patients (P