Abstract IA23: Allele-specific HLA loss and immune escape in lung cancer evolution

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Abstract In order to avoid immune predation, particularly in response to immunotherapy, tumors must acquire mechanisms to evade immune detection or withstand its activity. Disruption of human leukocyte antigen (HLA), which may lead to reduced neoantigen presentation, has been proposed as an immune escape strategy in many cancers, including lung cancer. A high proportion of cancer types have been found to downregulate HLA expression, potentially leading to the evasion of T cell-mediated destruction (Hicklin, 1999; Garrido, 2017) with reduced HLA expression associating with decreased overall survival and tumor progression (Mehta, 2008). Another irreversible means of HLA disruption is via loss of heterozygosity (LOH) at the HLA locus (Koopman, 2000). However, to date, the diversity of the HLA locus has impeded copy number analysis and determination of HLA loss. To investigate the prevalence, timing, and importance of HLA disruption, we developed LOHHLA (Loss Of Heterozygosity in Human Leukocyte Antigen), a computational tool to determine HLA allele-specific copy number from sequencing data. Supporting the notion that loss of antigen presentation may play an important role in immune evasion during tumor evolution, HLA LOH was identified in 40% of the NSCLC samples analyzed, frequently as a late event in tumor evolution and associated with a high subclonal neoantigen burden, increase in immune infiltration, and PD-L1 positivity. Characterizing HLA haplotype specific copy number with LOHHLA refines neoantigen prediction and may have implications for immunotherapeutic approaches targeting neoantigens. Citation Format: Nicholas McGranahan, Rachel Rosenthal, Crispin T. Hiley, Andrew J. Rowan, Thomas B.K. Watkins, Gareth A. Wilson, Nicolai J. Birkbak, Selvaraju Veeriah, Peter Van Loo, Javier Herrero, Charles Swanton. Allele-specific HLA loss and immune escape in lung cancer evolution [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr IA23.