Abstract 3788: Antigen presentation by MHC-I molecule and immune escape in acute myeloid leukemia with high burden of genomic aberrations

Abstract

Abstract Background: Antigen presentation is crucial for tumor immune response and MHC-I plays a key role. Solid and hematological tumors with high load of newly tumor associated antigens develop evading immune surveillance. A subset of patients with acute myeloid leukemia (AML), precisely ones with complex karyotype and TP53 alterations have a high load of mutation or genomic aberrations. In our study, we screened the entire genome of a large set of newly diagnosed AML to discover if MHC I antigen presentation is altered in the set of AML with a high neo-antigen load. Methods: We screened 300 samples of AML bone marrow at diagnosis from 3 hematological Institutions. We analyzed 636 single nucleotide polymorphism (SNP) arrays to detect karyotype aberration at genomic level; germline SNP arrays were performed in 114/300 patients, the remaining 186/300 were normalized with a reference pool of 222 healthy donors. Of the 300 patients, we collected clinical data and we tested TP53, IDH1, IDH2, FLT3, NPM1, DNMT3A and RUNX1 mutations according ordinary practice. Genes in MHC class I antigen presentation pathway were selected basing on Reactome. We considered MHC-I antigen presentation altered if pathway's alteration rate (altered genes in a pathway/gene in a pathway ratio) scored in the top 25% between all pathways. Results: Twenty out of 300 patients (6.7%) had loss of genes in MHC I antigen presentation (group A). Patients had alterations in one or more genes; overall, 53 genes were founded altered in our set. Patients in group A did not have differences in age or in white blood count at diagnosis compared with other patients in our set (group B). Group A was enriched for patients with of complex karyotype (14/20 patients, p<.001), isolated del(5q) (3/20) and for patients harboring TP53 mutation (11/20 patients, p<.001). In 280 patients (20 not tested), 70 patient had complex karyotype; 14/70 (20%, p<.001) patients with complex karyotype were from group A. Group A had a higher median burden of genomic than patients in group B (0.08 vs 0.04 alterations per pathway, p<.001). Patients in group A had a lower median overall survival (OS) than patients in group B (3.0 months vs 15.7 months, p<.001). Conclusion: We demonstrated that patients with MHCI alterations have a high chance to be TP53 mutated or to have complex karyotype; patients with complex karyotype have a high chance to harbor concomitant alterations in MHC I antigen presentation. In the set of AML with high burden of aberrations, MHC I alterations could be permissive for leukemia development toward immune escape. Our approach is a good candidate for further testing inside clinical trials to identify a cohort of patients that are unlikely to respond to immune check-point inhibitors within patients with larger sets of patients with high burden of alterations. Acknowledgements: ELN, AIL, AIRC, Regione-Università 2010-12, FP7 NGS-PTL, HARMONY, Fondazione del Monte BO e RA. Citation Format: Giovanni Marconi, Maria Chiara Fontana, Cristina Papayannidis, Mariachiara Abbenante, Antonella Padella, Giorgia Simonetti, Michele Cavo, Giovanni Martinelli. Antigen presentation by MHC-I molecule and immune escape in acute myeloid leukemia with high burden of genomic aberrations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3788.