Neoantigen quality predicts immunoediting in survivors of pancreatic cancer.

Cancer immunoediting1 is a hallmark of cancer2 that predicts that lymphocytes kill more immunogenic cancer cells to cause less immunogenic clones to dominate a population. Although proven in mice1,3, whether immunoediting occurs naturally in human cancers remains unclear. Here, to address this, we investigate how 70 human pancreatic cancers evolved over 10 years. We find that, despite having more time to accumulate mutations, rare long-term survivors of pancreatic cancer who have stronger T cell activity in primary tumours develop genetically less heterogeneous recurrent tumours with fewer immunogenic mutations (neoantigens). To quantify whether immunoediting underlies these observations, we infer that a neoantigen is immunogenic (high-quality) by two features-'non-selfness'  based on neoantigen similarity to known antigens4,5, and 'selfness'  based on the antigenic distance required for a neoantigen to differentially bind to the MHC or activate a T cell compared with its wild-type peptide. Using these features, we estimate cancer clone fitness as the aggregate cost of T cells recognizing high-quality neoantigens offset by gains from oncogenic mutations. With this model, we predict the clonal evolution of tumours to reveal that long-term survivors of pancreatic cancer develop recurrent tumours with fewer high-quality neoantigens. Thus, we submit evidence that that the human immune system naturally edits neoantigens. Furthermore, we present a model to predict how immune pressure induces cancer cell populations to evolve over time. More broadly, our results argue that the immune system fundamentally surveils host genetic changes to suppress cancer.

TULIP: A transformer-based unsupervised language model for interacting peptides and T cell receptors that generalizes to unseen epitopes.

The accurate prediction of binding between T cell receptors (TCR) and their cognate epitopes is key to understanding the adaptive immune response and developing immunotherapies. Current methods face two significant limitations: the shortage of comprehensive high-quality data and the bias introduced by the selection of the negative training data commonly used in the supervised learning approaches. We propose a method, Transformer-based Unsupervised Language model for Interacting Peptides and T cell receptors (TULIP), that addresses both limitations by leveraging incomplete data and unsupervised learning and using the transformer architecture of language models. Our model is flexible and integrates all possible data sources, regardless of their quality or completeness. We demonstrate the existence of a bias introduced by the sampling procedure used in previous supervised approaches, emphasizing the need for an unsupervised approach. TULIP recognizes the specific TCRs binding an epitope, performing well on unseen epitopes. Our model outperforms state-of-the-art models and offers a promising direction for the development of more accurate TCR epitope recognition models.

Innate-like T cell subset commitment in the murine thymus is independent of TCR characteristics and occurs during proliferation.

How T-cell receptor (TCR) characteristics determine subset commitment during T-cell development is still unclear. Here, we addressed this question for innate-like T cells, mucosal-associated invariant T (MAIT) cells, and invariant natural killer T (iNKT) cells. MAIT and iNKT cells have similar developmental paths, leading in mice to two effector subsets, cytotoxic (MAIT1/iNKT1) and IL17-secreting (MAIT17/iNKT17). For iNKT1 vs iNKT17 fate choice, an instructive role for TCR affinity was proposed but recent data argue against this model. Herein, we examined TCR role in MAIT and iNKT subset commitment through scRNAseq and TCR repertoire analysis. In our dataset of thymic MAIT cells, we found pairs of T-cell clones with identical amino acid TCR sequences originating from distinct precursors, one of which committed to MAIT1 and the other to MAIT17 fates. Quantitative in silico simulations indicated that the number of such cases is best explained by lineage choice being independent of TCR characteristics. Comparison of TCR features of MAIT1 and MAIT17 clonotypes demonstrated that the subsets cannot be distinguished based on TCR sequence. To pinpoint the developmental stage associated with MAIT sublineage choice, we demonstrated that proliferation takes place both before and after MAIT fate commitment. Altogether, we propose a model of MAIT cell development in which noncommitted, intermediate-stage MAIT cells undergo a first round of proliferation, followed by TCR characteristics-independent commitment to MAIT1 or MAIT17 lineage, followed by an additional round of proliferation. Reanalyzing a published iNKT TCR dataset, we showed that this model is also relevant for iNKT cell development.

Towards a quantitative theory of tolerance.

A cornerstone of the classical view of tolerance is the elimination of self-reactive T cells via negative selection in the thymus. However, high-throughput T cell receptor (TCR) sequencing data have so far failed to detect substantial signatures of negative selection in the observed repertoires. In addition, quantitative estimates as well as recent experiments suggest that the elimination of self-reactive T cells is at best incomplete. We discuss several recent theoretical ideas that might explain tolerance while being consistent with these observations, including collective decision-making through quorum sensing, and sensitivity to change through dynamic tuning and adaptation. We propose that a unified quantitative theory of tolerance should combine these elements to help to explain the plasticity of the immune system and its robustness to autoimmunity.

Evolutionary stability of antigenically escaping viruses.

Antigenic variation is the main immune escape mechanism for RNA viruses like influenza or SARS-CoV-2. While high mutation rates promote antigenic escape, they also induce large mutational loads and reduced fitness. It remains unclear how this cost-benefit trade-off selects the mutation rate of viruses. Using a traveling wave model for the coevolution of viruses and host immune systems in a finite population, we investigate how immunity affects the evolution of the mutation rate and other nonantigenic traits, such as virulence. We first show that the nature of the wave depends on how cross-reactive immune systems are, reconciling previous approaches. The immune-virus system behaves like a Fisher wave at low cross-reactivities, and like a fitness wave at high cross-reactivities. These regimes predict different outcomes for the evolution of nonantigenic traits. At low cross-reactivities, the evolutionarily stable strategy is to maximize the speed of the wave, implying a higher mutation rate and increased virulence. At large cross-reactivities, where our estimates place H3N2 influenza, the stable strategy is to increase the basic reproductive number, keeping the mutation rate to a minimum and virulence low.

Modeling and predicting the overlap of B- and T-cell receptor repertoires in healthy and SARS-CoV-2 infected individuals.

Adaptive immunity's success relies on the extraordinary diversity of protein receptors on B and T cell membranes. Despite this diversity, the existence of public receptors shared by many individuals gives hope for developing population-wide vaccines and therapeutics. Using probabilistic modeling, we show many of these public receptors are shared by chance in healthy individuals. This predictable overlap is driven not only by biases in the random generation process of receptors, as previously reported, but also by their common functional selection. However, the model underestimates sharing between repertoires of individuals infected with SARS-CoV-2, suggesting strong specific antigen-driven convergent selection. We exploit this discrepancy to identify COVID-associated receptors, which we validate against datasets of receptors with known viral specificity. We study their properties in terms of sequence features and network organization, and use them to design an accurate diagnostic tool for predicting SARS-CoV-2 status from repertoire data.

Inferring the T cell repertoire dynamics of healthy individuals.

The adaptive immune system is a diverse ecosystem that responds to pathogens by selecting cells with specific receptors. While clonal expansion in response to particular immune challenges has been extensively studied, we do not know the neutral dynamics that drive the immune system in the absence of strong stimuli. Here, we learn the parameters that underlie the clonal dynamics of the T cell repertoire in healthy individuals of different ages, by applying Bayesian inference to longitudinal immune repertoire sequencing (RepSeq) data. Quantifying the experimental noise accurately for a given RepSeq technique allows us to disentangle real changes in clonal frequencies from noise. We find that the data are consistent with clone sizes following a geometric Brownian motion and show that its predicted steady state is in quantitative agreement with the observed power-law behavior of the clone-size distribution. The inferred turnover time scale of the repertoire increases with patient age and depends on the clone size in some individuals.

Affinity maturation for an optimal balance between long-term immune coverage and short-term resource constraints.

In order to target threatening pathogens, the adaptive immune system performs a continuous reorganization of its lymphocyte repertoire. Following an immune challenge, the B cell repertoire can evolve cells of increased specificity for the encountered strain. This process of affinity maturation generates a memory pool whose diversity and size remain difficult to predict. We assume that the immune system follows a strategy that maximizes the long-term immune coverage and minimizes the short-term metabolic costs associated with affinity maturation. This strategy is defined as an optimal decision process on a finite dimensional phenotypic space, where a preexisting population of cells is sequentially challenged with a neutrally evolving strain. We show that the low specificity and high diversity of memory B cells-a key experimental result-can be explained as a strategy to protect against pathogens that evolve fast enough to escape highly potent but narrow memory. This plasticity of the repertoire drives the emergence of distinct regimes for the size and diversity of the memory pool, depending on the density of de novo responding cells and on the mutation rate of the strain. The model predicts power-law distributions of clonotype sizes observed in data and rationalizes antigenic imprinting as a strategy to minimize metabolic costs while keeping good immune protection against future strains.

Evolution and folding of repeat proteins.

Repeat proteins are made with tandem copies of similar amino acid stretches that fold into elongated architectures. These proteins constitute excellent model systems to investigate how evolution relates to structure, folding, and function. Here, we propose a scheme to map evolutionary information at the sequence level to a coarse-grained model for repeat-protein folding and use it to investigate the folding of thousands of repeat proteins. We model the energetics by a combination of an inverse Potts-model scheme with an explicit mechanistic model of duplications and deletions of repeats to calculate the evolutionary parameters of the system at the single-residue level. These parameters are used to inform an Ising-like model that allows for the generation of folding curves, apparent domain emergence, and occupation of intermediate states that are highly compatible with experimental data in specific case studies. We analyzed the folding of thousands of natural Ankyrin repeat proteins and found that a multiplicity of folding mechanisms are possible. Fully cooperative all-or-none transitions are obtained for arrays with enough sequence-similar elements and strong interactions between them, while noncooperative element-by-element intermittent folding arose if the elements are dissimilar and the interactions between them are energetically weak. Additionally, we characterized nucleation-propagation and multidomain folding mechanisms. We show that the global stability and cooperativity of the repeating arrays can be predicted from simple sequence scores.

Deep generative selection models of T and B cell receptor repertoires with soNNia.

Subclasses of lymphocytes carry different functional roles to work together and produce an immune response and lasting immunity. Additionally to these functional roles, T and B cell lymphocytes rely on the diversity of their receptor chains to recognize different pathogens. The lymphocyte subclasses emerge from common ancestors generated with the same diversity of receptors during selection processes. Here, we leverage biophysical models of receptor generation with machine learning models of selection to identify specific sequence features characteristic of functional lymphocyte repertoires and subrepertoires. Specifically, using only repertoire-level sequence information, we classify CD4+ and CD8+ T cells, find correlations between receptor chains arising during selection, and identify T cell subsets that are targets of pathogenic epitopes. We also show examples of when simple linear classifiers do as well as more complex machine learning methods.

Antigenic waves of virus-immune coevolution.

The evolution of many microbes and pathogens, including circulating viruses such as seasonal influenza, is driven by immune pressure from the host population. In turn, the immune systems of infected populations get updated, chasing viruses even farther away. Quantitatively understanding how these dynamics result in observed patterns of rapid pathogen and immune adaptation is instrumental to epidemiological and evolutionary forecasting. Here we present a mathematical theory of coevolution between immune systems and viruses in a finite-dimensional antigenic space, which describes the cross-reactivity of viral strains and immune systems primed by previous infections. We show the emergence of an antigenic wave that is pushed forward and canalized by cross-reactivity. We obtain analytical results for shape, speed, and angular diffusion of the wave. In particular, we show that viral-immune coevolution generates an emergent timescale, the persistence time of the wave's direction in antigenic space, which can be much longer than the coalescence time of the viral population. We compare these dynamics to the observed antigenic turnover of influenza strains, and we discuss how the dimensionality of antigenic space impacts the predictability of the evolutionary dynamics. Our results provide a concrete and tractable framework to describe pathogen-host coevolution.

Immune fingerprinting through repertoire similarity.

Immune repertoires provide a unique fingerprint reflecting the immune history of individuals, with potential applications in precision medicine. However, the question of how personal that information is and how it can be used to identify individuals has not been explored. Here, we show that individuals can be uniquely identified from repertoires of just a few thousands lymphocytes. We present "Immprint," a classifier using an information-theoretic measure of repertoire similarity to distinguish pairs of repertoire samples coming from the same versus different individuals. Using published T-cell receptor repertoires and statistical modeling, we tested its ability to identify individuals with great accuracy, including identical twins, by computing false positive and false negative rates < 10-6 from samples composed of 10,000 T-cells. We verified through longitudinal datasets that the method is robust to acute infections and that the immune fingerprint is stable for at least three years. These results emphasize the private and personal nature of repertoire data.

Dynamical Information Synergy in Biochemical Signaling Networks.

Biological cells encode information about their environment through biochemical signaling networks that control their internal state and response. This information is often encoded in the dynamical patterns of the signaling molecules, rather than just their instantaneous concentrations. Here, we analytically calculate the information contained in these dynamics for a number of paradigmatic cases in the linear regime, for both static and time-dependent input signals. When considering oscillatory output dynamics, we report on the emergence of synergy between successive measurements, meaning that the joint information in two measurements exceeds the sum of the individual information. We extend our analysis numerically beyond the scope of linear input encoding to reveal synergetic effects in the cases of frequency or damping modulation, both of which are relevant to classical biochemical signaling systems.

Learning the statistics and landscape of somatic mutation-induced insertions and deletions in antibodies.

Affinity maturation is crucial for improving the binding affinity of antibodies to antigens. This process is mainly driven by point substitutions caused by somatic hypermutations of the immunoglobulin gene. It also includes deletions and insertions of genomic material known as indels. While the landscape of point substitutions has been extensively studied, a detailed statistical description of indels is still lacking. Here we present a probabilistic inference tool to learn the statistics of indels from repertoire sequencing data, which overcomes the pitfalls and biases of standard annotation methods. The model includes antibody-specific maturation ages to account for variable mutational loads in the repertoire. After validation on synthetic data, we applied our tool to a large dataset of human immunoglobulin heavy chains. The inferred model allows us to identify universal statistical features of indels in heavy chains. We report distinct insertion and deletion hotspots, and show that the distribution of lengths of indels follows a geometric distribution, which puts constraints on future mechanistic models of the hypermutation process.

Detecting T cell receptors involved in immune responses from single repertoire snapshots.

Hypervariable T cell receptors (TCRs) play a key role in adaptive immunity, recognizing a vast diversity of pathogen-derived antigens. Our ability to extract clinically relevant information from large high-throughput sequencing of TCR repertoires (RepSeq) data is limited, because little is known about TCR-disease associations. We present Antigen-specific Lymphocyte Identification by Clustering of Expanded sequences (ALICE), a statistical approach that identifies TCR sequences actively involved in current immune responses from a single RepSeq sample and apply it to repertoires of patients with a variety of disorders - patients with autoimmune disease (ankylosing spondylitis [AS]), under cancer immunotherapy, or subject to an acute infection (live yellow fever [YF] vaccine). We validate the method with independent assays. ALICE requires no longitudinal data collection nor large cohorts, and it is directly applicable to most RepSeq datasets. Its results facilitate the identification of TCR variants associated with diseases and conditions, which can be used for diagnostics and rational vaccine design.

Optimal prediction with resource constraints using the information bottleneck.

Responding to stimuli requires that organisms encode information about the external world. Not all parts of the input are important for behavior, and resource limitations demand that signals be compressed. Prediction of the future input is widely beneficial in many biological systems. We compute the trade-offs between representing the past faithfully and predicting the future using the information bottleneck approach, for input dynamics with different levels of complexity. For motion prediction, we show that, depending on the parameters in the input dynamics, velocity or position information is more useful for accurate prediction. We show which motion representations are easiest to re-use for accurate prediction in other motion contexts, and identify and quantify those with the highest transferability. For non-Markovian dynamics, we explore the role of long-term memory in shaping the internal representation. Lastly, we show that prediction in evolutionary population dynamics is linked to clustering allele frequencies into non-overlapping memories.

Probing T-cell response by sequence-based probabilistic modeling.

With the increasing ability to use high-throughput next-generation sequencing to quantify the diversity of the human T cell receptor (TCR) repertoire, the ability to use TCR sequences to infer antigen-specificity could greatly aid potential diagnostics and therapeutics. Here, we use a machine-learning approach known as Restricted Boltzmann Machine to develop a sequence-based inference approach to identify antigen-specific TCRs. Our approach combines probabilistic models of TCR sequences with clone abundance information to extract TCR sequence motifs central to an antigen-specific response. We use this model to identify patient personalized TCR motifs that respond to individual tumor and infectious disease antigens, and to accurately discriminate specific from non-specific responses. Furthermore, the hidden structure of the model results in an interpretable representation space where TCRs responding to the same antigen cluster, correctly discriminating the response of TCR to different viral epitopes. The model can be used to identify condition specific responding TCRs. We focus on the examples of TCRs reactive to candidate neoantigens and selected epitopes in experiments of stimulated TCR clone expansion.

NoisET: Noise Learning and Expansion Detection of T-Cell Receptors.

High-throughput sequencing of T- and B-cell receptors makes it possible to track immune repertoires across time, in different tissues, in acute and chronic diseases and in healthy individuals. However, quantitative comparison between repertoires is confounded by variability in the read count of each receptor clonotype due to sampling, library preparation, and expression noise. We review methods for accounting for both biological and experimental noise and present an easy-to-use python package NoisET that implements and generalizes a previously developed Bayesian method. It can be used to learn experimental noise models for repertoire sequencing from replicates, and to detect responding clones following a stimulus. We test the package on different repertoire sequencing technologies and data sets. We review how such approaches have been used to identify responding clonotypes in vaccination and disease data. Availability: NoisET is freely available to use with source code at github.com/statbiophys/NoisET.

Learning the heterogeneous hypermutation landscape of immunoglobulins from high-throughput repertoire data.

Somatic hypermutations of immunoglobulin (Ig) genes occurring during affinity maturation drive B-cell receptors' ability to evolve strong binding to their antigenic targets. The landscape of these mutations is highly heterogeneous, with certain regions of the Ig gene being preferentially targeted. However, a rigorous quantification of this bias has been difficult because of phylogenetic correlations between sequences and the interference of selective forces. Here, we present an approach that corrects for these issues, and use it to learn a model of hypermutation preferences from a recently published large IgH repertoire dataset. The obtained model predicts mutation profiles accurately and in a reproducible way, including in the previously uncharacterized Complementarity Determining Region 3, revealing that both the sequence context of the mutation and its absolute position along the gene are important. In addition, we show that hypermutations occurring concomittantly along B-cell lineages tend to co-localize, suggesting a possible mechanism for accelerating affinity maturation.

How a well-adapting immune system remembers.

An adaptive agent predicting the future state of an environment must weigh trust in new observations against prior experiences. In this light, we propose a view of the adaptive immune system as a dynamic Bayesian machinery that updates its memory repertoire by balancing evidence from new pathogen encounters against past experience of infection to predict and prepare for future threats. This framework links the observed initial rapid increase of the memory pool early in life followed by a midlife plateau to the ease of learning salient features of sparse environments. We also derive a modulated memory pool update rule in agreement with current vaccine-response experiments. Our results suggest that pathogenic environments are sparse and that memory repertoires significantly decrease infection costs, even with moderate sampling. The predicted optimal update scheme maps onto commonly considered competitive dynamics for antigen receptors.