Prognostic value of HLA-I homozygosity in patients with non-small cell lung cancer treated with single agent immunotherapy

Abstract

BackgroundWe aimed to assess the impact of genomic human leukocyte antigen (HLA)-I/II homozygosity on the survival benefit of patients with unresectable locally advanced, metastatic non-small lung cancer treated by single-agent programmed cell death protein-1/programmed death ligand 1 (PD1/PDL1) inhibitors.MethodsWe collected blood from 170 patients with advanced lung cancer treated with immunotherapy at two major oncology centers in Western Australia. Genomic DNA was extracted from white blood cells and used for HLA-I/II high-resolution typing. HLA-I/II homozygosity was tested for association with survival outcomes. Univariable and multivariable Cox regression models were constructed to determine whether HLA homozygosity was an independent prognostic factor affecting Overall Survival (OS) and Progression Free Survival (PFS). We also investigated the association between individual HLA-A and -B supertypes with OS.ResultsHomozygosity at HLA-I loci, but not HLA-II, was significantly associated with shorter OS (HR=2.17, 95% CI 1.13 to 4.17, p=0.02) in both univariable and multivariable analysis. The effect of HLA-I homozygosity in OS was particularly relevant for patients with tumors expressing PDL1 ≥50% (HR=3.93, 95% CI 1.30 to 11.85, p<0.001). The adverse effect of HLA-I homozygosity on PFS was only apparent after controlling for interactions between PDL1 status and HLA-I genotype (HR=2.21, 95% CI 1.04 to 4.70, p=0.038). The presence of HLA-A02 supertype was the only HLA-I supertype to be associated with improved OS (HR=0.56, 95% CI 0.34 to 0.93, p=0.023).ConclusionOur results suggest that homozygosity at ≥1 HLA-I loci is associated with short OS and PFS in patients with advanced non-small cell lung cancer with PDL1 ≥50% treated with single-agent immunotherapy. Carriers of HLA-A02 supertype reported better survival outcomes in this cohort of patients.

Association of HLA class I homozygosity with unfavorable clinical outcomes in patients with non-small cell lung cancer treated with chemo-immunotherapy or immunotherapy as first-line therapy

“…Another study involving patients with advanced NSCLC treated with ICIs with or without chemotherapy evaluated HLA-I zygosity as a prognostic biomarker for NSLCL 17 Most recently, another study involving 161 NSCLC treated with ICI monotherapy demonstrated the association of HLA-I homozygosity with poor survival outcome 22 . This was remarkable particularly in patients who expressed PDL1 greater than 50% (HR=3.93, 95% CI 1.30-11.85, p<0.001).…”

“…It demonstrated the association of supertype B44 with increased survival outcome, and supertype B62 with decreased survival outcome 16 . The other recent study demonstrated the association of supertype HLA-A02 with better survival outcomes 22 .…”

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

“…In addition to the study by Chowell et al [14], two other studies have recently been published in advanced non-small cell lung cancer. The ndings from Abed et al [22] suggest that homozygosity at one or more HLA-I loci was associated with shorter OS and PFS in patients with advanced non-small cell lung cancer with PDL1 score ≥ 50%. The study also found that carriers of HLA-A02 supertype had better survival outcomes.…”

“…Several biomarkers like tumour mutational burden, PDL-1 expression, microsatellite instability (MSI) status, neoantigen load and HLA status have been recently evaluated to determine their utility to predict response to ICI therapy[6, 14,22]. We have previously published on the utility of circulating tumour cell PDL1 expression [24] and serum vascular endothelial growth factor (VEGF) levels [25] as potential bloodbased predictive biomarkers of response to anti-PD1 therapy in advanced melanoma.…”

“…QIAamp DNA Blood Maxi Kit (Qiagen, Hilden, Germany) was used for DNA extraction. Extracted DNA was used for high-resolution HLA typing at the Institute of Immunology and Infectious disease (IIID) at Murdoch University as previously reported [22]. HLA testing at IIID has been accredited by the American Society for Histocompatibility and Immunogenetics (ASHI) and the National Association of Testing Authorities (NATA) [23].…”