LAUSR

Simple Summary Immunosurveillance of cancer is mediated by T cell-based recognition of tumor-associated antigens, i.e., short peptides that are presented on the surface of cells on human leukocyte antigen (HLA) molecules. This encourages the analysis of the entirety of HLA-presented peptides, the so-called immunopeptidome, of malignant and benign cells, in order to identify novel therapeutic targets presented exclusively on malignant cells. In the present study, we aim to investigate the role of previously described immunopeptidome-defined antigen presentation in chronic lymphocytic leukemia (CLL) patients for clinical characteristics and disease outcome. We observed that higher yields of presented total and CLL-exclusive peptides were associated with a more favorable disease course, suggesting efficient immunosurveillance in a subgroup of patients and the possibility of further investigating T cell-based therapeutic approaches for CLL. Abstract Chronic lymphocytic leukemia (CLL) is characterized by recurrent relapses and resistance to treatment, even with novel therapeutic approaches. Despite being considered as a disease with low mutational burden and thus poor immunogenic, CLL seems to retain the ability of eliciting specific T cell activation. Accordingly, we recently found non-mutated tumor-associated antigens to play a central role in CLL immunosurveillance. Here, we investigated the association of total and CLL-exclusive HLA class I and HLA class II peptide presentation in the mass spectrometry-defined immunopeptidome of leukemic cells with clinical features and disease outcome of 57 CLL patients. Patients whose CLL cells present a more diverse immunopeptidome experienced fewer relapses. During the follow-up phase of up to 10 years, patients with an HLA class I-restricted presentation of high numbers of total and CLL-exclusive peptides on their malignant cells showed a more favorable disease course with a prolonged progression-free survival (PFS). Overall, our results suggest the existence of an efficient T cell-based immunosurveillance mediated by CLL-associated tumor antigens, supporting ongoing efforts in developing T cell-based immunotherapeutic strategies for CLL.