MHC-I Antigen Presentation Role in Immune Escape of Acute Myeloid Leukemia with High Burden of Genomic Aberration

Background:

MHC I antigen presentation is a key pathway in immune response against tumor. It involves degradation of tumor associated antigens, folding and loading of immune epitopes on MHC-I molecules and MHC-I associated presentation on tumor cell surface. Evidence suggests that solid and hematological tumors with high mutational burden or high load in newly tumor associated antigens needs to escape immune surveillance to develop. Acute myeloid leukemia (AML) is not usually believed to be an immunogenic tumor, but patients with complex karyotype, or patients with TP53 alterations have a hypothetical high load of mutation or genomic aberrations.

Our study aims to check the entire genome of a large set of newly diagnosed AML to discover if alterations in MHC I antigen presentation could explain the immune escape of the small set of out-layer AML with a high neo-antigen load.

Method:

We collected 300 bone marrow samples of AML patients at diagnosis from 3 hematological Institutions. Affymetrix Cytoscan HD or 6.0 single nucleotide polymorphism (SNP) array was performed for every samples. Germline SNP array was performed in 114/300 patients, the remaining 186/300 were normalized with a reference pool of 222 healthy donors. Clinical data were collected retrospectively, TP53 , IDH1 , IDH2 , FLT3 , NPM1 , DNMT3A and RUNX1 mutations were tested at diagnosis according ordinary practice. We selected genes involved in MHC class I antigen presentation basing on Reactome pathway. For each patient, 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 4^th quartile in the alterations rate of all pathways.

Results:

Twenty out of 300 patients (6.7%) had alteration in MHC I antigen presentation. Patients had alterations in one or more genes: overall 53 genes was founded altered in our set.

Patients with alteration in MHC I antigen presentation (group A) did not have differences in age (figure 1a), and in white blood count at diagnosis (figure 1b) compared with other patients in our set (group B). Group A had a prevalence of complex karyotype (14/20 patients, p<.001), and isolated del(5q) (3/30) and abundance in patients harboring TP53 mutation (11/20 patients, p<.001). In group A, a patient harbored FLT3 ITD mutation, a patient IDH2 mutation and 3 patients out of 4 patients tested harbored RUNX1 mutation. In group B, 39/271 patients (13.9%, 9 patients had missing data) harbored TP53 mutation and 56/280 patients had a complex karyotype (29.0%, 9 patients had missing data). Patients in group A had a higher burden of alterations per pathway than patients in group B (0.08 vs 0.04, p<.001).

Patients in group A had a median overall survival (OS) of 3.0 months, group B had an OS of 15.7 months (figure 1c, p<.001). MHC class I alteration did not result an essential factor in Cox-hazard ratio model with age, induction therapy, karyotype at diagnosis, TP53, FLT3 and NPM1 mutations.

Conclusion:

MHC I alteration conferred poor OS at patients in group A; as expected, dismal OS was not confirmed in a multivariable model. We demonstrate that MHC I alteration frequently co-occurred with TP53 mutations and complex karyotype. MHC I alteration was not proved to be a driver alteration in AML, but in the subset of AML with a high number of karyotype aberrations it could favor immune escape and be permissive toward leukemia development and maintenance. Furthermore our approach could be useful in identifying a cohort of patients that are unlikely to respond to immune check-point inhibitors or similar drugs for the dysfunctions in antigen presentation, and a second cohort of patients with TP53 alteration and/or complex karyotype in which these drugs could be administered.

Acknowledgments: ELN, AIL, AIRC, project Regione-Università 2010-12 (L. Bolondi), FP7 NGS-PTL project, HARMONY project, Fondazione del Monte BO e RA project.

Figure 1

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