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.
A. Dumitrescu, Dani Korpela, Adrian M. Bebenek et al.· bioRxiv· 0 citations
Occasional complete responses to immune checkpoint inhibitor therapy demonstrate that acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) can be immune-sensitive when appropriately targeted. Here, we analyzed AML/MDS patients (n=14) treated with the anti-TIM3 sabatolimab and the hypomethylating agent decitabine in a phase Ib clinical trial (NCT03066648) using single-cell RNA and T cell receptor (TCR) sequencing (n=6) and functional co-culture assays. Unlike T cell-restricted CTLA4 and PD1, TIM3 was broadly expressed across natural killer (NK)-cell, myeloid-cell, and T-cell populations. Therapy induced expansion of cytotoxic NK-cell subsets and enhanced type I interferon signaling. Fewer than 1% of bone marrow CD8+ T cells displayed a canonical exhaustion phenotype, and treatment preferably expanded small CD8+ T-cell clones in responders. Responders exhibited greater expansion of cytotoxic CD4+ T cells and B cells, as exemplified by a patient with pre-existing CD4+ T-cell large granular lymphocyte leukemia (T-LGLL) achieving an outstanding complete response lasting 23 months. Over 20% of this patient's lymphocytes were T-LGLL cells expressing a TCR capable of recognizing autologous blasts. Overall, our results suggest that anti-TIM3 combined with decitabine engages a distinct mechanism of immune activation compared to anti-PD1 and anti-CTLA4, preferentially expanding NK-cell and CD4+ T-cell populations.
Jani Huuhtanen, S. Forstén, B. Ford et al.· Cancer immunology research· 0 citations