HLA Genotype is Associated With Clinical Outcomes to anti-PD1 Therapy in Advanced Melanoma

Abstract Background:Predictive biomarkers of response to immune checkpoint inhibitors (ICI) are currently being evaluated in many studies. We evaluated whether germline Human Leukocyte Antigen (HLA) status can influence the response to immunotherapy.Materials and Methods:Advanced melanoma patients undergoing treatment with pembrolizumab were recruited between August 2014 to January 2020. 121 patients were recruited, with a median follow up of 40.1 months. We dichotomised the cohort based on homozygosity in one or more HLA-I alleles (n=29) and those with maximal heterozygosity (n=84).Results:Our analysis did not show any association between HLA-I homozygosity and PFS (HR 1.06, 95% CI: 0.60-1.87, p = 0.83) or OS (HR 0.98, 95% CI: 0.51-1.191, p = 0.97). Similarly, we did not find any impact of HLA-II homozygosity (46 homozygous and 67 heterozygous) on PFS (HR 1.08, 95% CI: 0.66-1.79, p = 0.741) or OS (HR 1.52, 95% CI: 0.80-2.85, p = 0.19). Notably, the HLA-B27 supertype was associated with reduced PFS (HR 2.19, 95% CI: 1.19-4.02, p=0.02), and OS (HR:2.20, 95% CI:1.85-4.47, p=0.0075). Multivariate analyses confirmed that the HLA-B27 genotype is an independent predictor of shorter PFS and OS. The HLA-B27 association with reduced OS was validated in an independent cohort of 114 cases from the MSK-IMPACT cohort (HR 3.17, 95% CI: 1.01-10.01, p=0.01).Conclusions:Patients with HLA-B27 supertype have worse prognosis compared to non-carriers and may predict reduced response to ICI therapy.