Jennifer G. Abelin

Peptide-HLA II interaction prediction for post-translationally modified peptides

CD4+ T cells recognize peptides presented by human leukocyte antigen (HLA) II, implementing a fundamental mediation mechanism of the adaptive immune system. Although post-translational modifications (PTMs) alter immune responses, PTM-peptide-HLA interaction prediction remains challenging due to data scarcity resulting from substoichiometric levels of PTMs. To overcome this, we developed PepChem, a deep learning model utilizing novel, molecular-level peptide representations that enable predictions for sidechain modifications. Using monoallelic datasets that we reanalyze for PTMs of interest, we show accurate predictions on PTMs that were unseen during training. Furthermore, we introduce a novel training protocol that improves PTM-peptide generalization compared to conventional methods. We predict and experimentally validate citrullination-induced binding increase of rheumatoid arthritis (RA)-linked peptides to HLA II risk allele DRB1*04:01. This framework bridges the critical gap in PTM-aware immune recognition prediction, with immediate applications in autoimmunity, cancer, and infectious disease.

Latent effector T cells mediate immunotherapy responses in the bone marrow microenvironment.

T cell-mediated immune surveillance is critical for cancer control, yet its role in bone marrow malignancies remains poorly understood. Here, we integrate TCR profiling, HLA immunopeptidomics, and functional screening to characterize tumor-reactive T cells in the bone marrow of patients with multiple myeloma (MM) and acute myeloid leukemia (AML). These cells are transcriptionally defined by a conserved effector program distinct from the exhausted phenotype of tumor-reactive T cells in solid cancers. Immunopeptidomic profiling reveals a partially shared antigen landscape enriched for noncanonical peptides driving convergent TCR responses. We develop TFiT (tumor-reactive features in T cells), a transcriptional classifier that identifies these cells and stratifies immunotherapy, but not chemotherapy, response across independent MM and AML cohorts, supporting its specificity for T cell-mediated tumor control. These findings reveal a latent but activatable anti-tumor T cell compartment in bone marrow malignancies and provide a framework for engaging endogenous immunity in MM and AML.

Tertiary lymphoid structures harbour stem-like tumour-specific T cells