Surface proteomics reveals novel potentiel AML antigens for immunitherapeutic targeting

Résumé

Compared to solid tumors, antibody-based immunotherapy is underexploited in acute myeloid leukemia (AML), likely due to the limited availability of targetable surface antigens specifically expressed on AML cells. While targeted immunotherapies hold great promise, their development inexorably depends on the identification of cell surface antigens selectively expressed by cancer cells. The identification of such antigens has been challenging due to the characteristic hydrophobicity of plasma membrane proteins. Another level of complexity is brought by the fact that AML is a heterogeneous disease comprised of different subgroups with associated prognosis ranging from favorable to adverse. In order to identify novel AML antigens to be targeted using immunotherapeutic approaches, we have analysed the surface proteome of a collection of 100 primary human AML specimens, enriched in poor prognosis AML samples. These analyses revealed that AML subgroups have distinct surfaceome signatures. We also confirmed the expression of known AML markers at the surface of specific AML subgroups. Our search for novel AML antigens focused on four poor prognosis AML subgroups - MLL-rearranged, complex karyotype, RUNX1-mutated and normal karyotype with NPM1, DNMT3A and FLT3 (ITD) mutations. We identified proteins selectively expressed at the surface of AML cells from these subgroups. Analysis of the whole cohort of specimens also identified known and novel pan AML antigens. Single cell RNA-sequencing analysis of aforementioned subgroup-specific and pan AML antigens revealed that many of these are expressed by the vast majority of blast populations within primary AML specimens, including most primitive ones. Overall, these results suggest that studying the surface proteome of AML cells has the potential to reveal promising AML antigens to be targeted using immunotherapeutic approaches.,