A T-cell Receptor (TCR) is a specialized protein that is located on the surface of T-cells, which are a type of white blood cell crucial for the immune system. TCRs play a fundamental role in the adaptive immune response by allowing T-cells to recognize and respond to specific antigens. Antigens are molecular structures found on the surface of pathogens (such as viruses or bacteria) or abnormal cells. TCRs are part of the T-cell’s membrane and are involved in binding to specific antigens, triggering signaling pathways that lead to immune responses.

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T-Cell Receptor Optimization with Reinforcement Learning and Mutation Polices for Precision Immunotherapy

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T cells monitor the health status of cells by identifying foreign peptides displayed on their surface. T-cell receptors (TCRs), which are protein complexes found on the surface of T cells, are able to bind to these peptides. This process is known as TCR recognition and constitutes a key step for immune response. Optimizing TCR sequences for TCR recognition represents a fundamental step towards the development of personalized treatments to trigger immune responses killing cancerous or virus-infected cells. In this paper, we formulated the search for these optimized TCRs as a reinforcement learning (RL) problem and presented a framework TCRPPO with a mutation policy using proximal policy optimization. TCRPPO mutates TCRs into effective ones that can recognize given peptides. TCRPPO leverages a reward function that combines the likelihoods of mutated sequences being valid TCRs measured by a new scoring function based on deep autoencoders, with the probabilities of mutated sequences recognizing peptides from a peptide-TCR interaction predictor. We compared TCRPPO with multiple baseline methods and demonstrated that TCRPPO significantly outperforms all the baseline methods to generate positive binding and valid TCRs. These results demonstrate the potential of TCRPPO for both precision immunotherapy and peptide-recognizing TCR motif discovery.

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On TCR Binding Predictors Failing to Generalize to Unseen Peptides

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Several recent studies investigate TCR-peptide/-pMHC binding prediction using machine learning or deep learning approaches. Many of these methods achieve impressive results on test sets, which include peptide sequences that are also included in the training set. In this work, we investigate how state of the-art deep learning models for TCR-peptide/-pMHC binding prediction generalize to unseen peptides. We create a dataset including positive samples from IEDB, VDJdb, McPAS-TCR, and the MIRA set, as well as negative samples from both randomization and 10X Genomics assays. We name this collection of samples TChard. We propose the hard split, a simple heuristic for training/test split, which ensures that test samples exclusively present peptides that do not belong to the training set. We investigate the effect of different training/test splitting techniques on the models’ test performance, as well as the effect of training and testing the models using mismatched negative samples generated randomly, in addition to the negative samples derived from assays. Our results show that modern deep learning methods fail to generalize to unseen peptides. We provide an explanation why this happens and verify our hypothesis on the TChard dataset. We then conclude that robust prediction of TCR recognition is still far for being solved.

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T-Cell Receptor-Peptide Interaction Prediction with Physical Model Augmented Pseudo-Labeling

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Predicting the interactions between T-cell receptors (TCRs) and peptides is crucial for the development of personalized medicine and targeted vaccine in immunotherapy. Current datasets for training deep learning models of this purpose remain constrained without diverse TCRs and peptides. To combat the data scarcity issue presented in the current datasets, we propose to extend the training dataset by physical modeling of TCR-peptide pairs. Specifically, we compute the docking energies between auxiliary unknown TCR-peptide pairs as surrogate training labels. Then, we use these extended example-label pairs to train our model in a supervised fashion. Finally, we find that the AUC score for the prediction of the model can be further improved by pseudo-labeling of such unknown TCR-peptide pairs (by a trained teacher model), and re-training the model with those pseudo-labeled TCR-peptide pairs. Our proposed method that trains the deep neural network with physical modeling and data-augmented pseudo-labeling improves over baselines in the available two datasets. We also introduce a new dataset that contains over 80,000 unknown TCR-peptide pairs with docking energy scores.

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