Abstract 867P
Background
Germline variation may influence anti-tumour immune responses. Recent studies suggest that polygenic scores (PGS) for autoimmune disease risk are associated with immune-related adverse events in patients (pts) treated with anti-PD(L)-1 therapy (anti-PD1) but the role of PGS in melanoma remains unexplored. We evaluated associations between PGS for vitiligo (VIT) and hypothyroidism (HYPOT) and melanoma molecular and clinical traits.
Methods
PGS for VIT (42 variants) and HYPOT (134 variants) were derived from genome-wide association studies of 29,752 VIT/HYPOT cases + 423,473 controls. The Cancer Genome Atlas (TCGA) melanoma pts (TCGA SKCM; n = 443) were assigned PGS for VIT/HYPOT using their blood genotypes and associations between PGS and tumour gene expression, immune cell infiltrates, and survival examined. Tumour infiltration of 22 immune cell types was quantified by CIBERSORT. Gene expression changes in Hallmark pathways were evaluated by gene set enrichment analysis (GSEA), with false discovery rate (FDR) control. Cox models adjusted for age, sex, and stage were used for survival analyses. PGS-linked differentially expressed pathways in TCGA SKCM were assessed for association by GSEA with anti-PD1 response in on-treatment biopsies with transcriptomic data in an independent cohort of 54 melanoma pts.
Results
In TCGA SKCM, increased polygenic risks of VIT and HYPOT were associated with longer PFS (HR, 95% CI: VIT 0.84, 0.74-0.95; HYPOT 0.90, 0.80-1.01). VIT PGS was associated with increased CD8+ T cells (P = 0.03) and downregulated expression of the G2M cell cycle pathway (FDR = 6e-4). HYPOT PGS was associated with upregulation of interferon α (FDR = 3e-7) and γ (FDR = 2e-6) pathways. Genes driving pathway enrichments in TCGA SKCM were associated with anti-PD1 response on evaluation for expression in on-treatment samples in the independent cohort (FDR < 0.005).
Conclusions
PGS for autoimmune disease associate with PFS and intra-tumour pathway-level transcriptomic changes predictive of anti-PD1 response in melanoma. Since germline PGS can be measured pre-treatment, this may inform prognosis and patient selection if replicated in larger cohorts.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
UK Research and Innovation.
Disclosure
T. Robinson: Non-Financial Interests, Personal, Other, Educational grants: Daiichi Sankyo; Non-Financial Interests, Personal, Invited Speaker, Educational grants: Amgen. All other authors have declared no conflicts of interest.