T cell epitope mapping reveals immunodominance of evolutionarily conserved regions within SARS-CoV-2 proteome.

Understanding the breadth and functional profile of T cell responses is crucial for assessing their role in immune surveillance of emerging SARS-CoV-2 variants. Sampling healthy individuals, we profiled the kinetics and polyfunctionality of T cell immunity elicited by mRNA vaccination. Modeling of anti-spike T cell responses against ancestral and variant strains suggested epitope immunodominance and cross-reactivity as major predictive determinants of T cell immunity.

Deciphering the Code of Viral-Host Adaptation Through Maximum-Entropy Nucleotide Bias Models.

How viruses evolve largely depends on their hosts. To quantitatively characterize this dependence, we introduce Maximum Entropy Nucleotide Bias models (MENB) learned from single, di- and tri-nucleotide usage of viral sequences that infect a given host. We first use MENB to classify the viral family and the host of a virus from its genome, among four families of ssRNA viruses and three hosts.

Mis-splicing-derived neoantigens and cognate TCRs in splicing factor mutant leukemias.

Mutations in RNA splicing factors are prevalent across cancers and generate recurrently mis-spliced mRNA isoforms. Here, we identified a series of bona fide neoantigens translated from highly stereotyped splicing alterations promoted by neomorphic, leukemia-associated somatic splicing machinery mutations. We utilized feature-barcoded peptide-major histocompatibility complex (MHC) dextramers to isolate neoantigen-reactive T cell receptors (TCRs) from healthy donors, patients with active myeloid malignancy, and following curative allogeneic stem cell transplant.

An inflammatory biomarker signature of response to CAR-T cell therapy in non-Hodgkin lymphoma.

Disease progression is a substantial challenge in patients with non-Hodgkin lymphoma (NHL) undergoing chimeric antigen receptor T cell (CAR-T) therapy. Here we present InflaMix (INFLAmmation MIXture Model), an unsupervised quantitative model integrating 14 pre-CAR-T infusion laboratory and cytokine measures capturing inflammation and end-organ function. Developed using a cohort of 149 patients with NHL, InflaMix revealed an inflammatory signature associated with a high risk of CAR-T treatment failure, including increased hazard of death or relapse (hazard ratio, 2.

Pan-cancer multi-omic model of LINE-1 activity reveals locus heterogeneity of retrotransposition efficiency.

Somatic mobilization of LINE-1 (L1) has been implicated in cancer etiology. We analyzed a recent TCGA data release comprised of nearly 5000 pan-cancer paired tumor-normal whole-genome sequencing (WGS) samples and ~9000 tumor RNA samples. We developed TotalReCall an improved algorithm and pipeline for detection of L1 retrotransposition (RT), finding high correlation between L1 expression and "RT burden" per sample.

Restoration of the Tumor Suppressor Function of Y220C-Mutant p53 by Rezatapopt, a Small-Molecule Reactivator.

Unlabelled: Restoration of the tumor suppressor function of tumor-associated p53 mutants, including the Y220C substitution, has posed a significant challenge for therapeutic discovery. In this study, we describe rezatapopt (PC14586), part of a series of compounds designed to reactivate the p53 Y220C mutant. These compounds restore p53 tumor suppressor function by correcting its conformation and enabling it to bind DNA and activate downstream target genes, thus inducing antiproliferative changes in tumor cells.

LINE-1 ORF1p Mimics Viral Innate Immune Evasion Mechanisms in Pancreatic Ductal Adenocarcinoma.

This study uncovers PDAC-specific mechanisms that dampen immune responses to viral-repeat RNA via long interspersed nuclear element 1 ORF1p. Suppression of ORF1p activates antiviral responses, reducing tumor growth and epithelial-mesenchymal transition. High ORF1p expression correlates with poor prognosis, highlighting its potential as a therapeutic target for PDAC.

Terminal differentiation and persistence of effector regulatory T cells essential for preventing intestinal inflammation.

Regulatory T (T) cells are a specialized CD4 T cell lineage with essential anti-inflammatory functions. Analysis of T cell adaptations to non-lymphoid tissues that enable their specialized immunosuppressive and tissue-supportive functions raises questions about the underlying mechanisms of these adaptations and whether they represent stable differentiation or reversible activation states. Here, we characterize distinct colonic effector T cell transcriptional programs.

Chronic Viral Mimicry Induction following p53 Loss Promotes Immune Evasion.

Our landmark discovery of viral mimicry characterized repetitive elements as immunogenic stimuli that cull cancer cells. If expressed repetitive elements cull cancer cells, why does every human cancer express repetitive elements? Our report offers an exciting advancement toward understanding this paradox and how to exploit this mechanism for cancer interception. See related commentary by Murayama and Cañadas, p.

Cancer cells restrict immunogenicity of retrotransposon expression via distinct mechanisms.

To thrive, cancer cells must navigate acute inflammatory signaling accompanying oncogenic transformation, such as via overexpression of repeat elements. We examined the relationship between immunostimulatory repeat expression, tumor evolution, and the tumor-immune microenvironment. Integration of multimodal data from a cohort of pancreatic ductal adenocarcinoma (PDAC) patients revealed expression of specific Alu repeats predicted to form double-stranded RNAs (dsRNAs) and trigger retinoic-acid-inducible gene I (RIG-I)-like-receptor (RLR)-associated type-I interferon (IFN) signaling.

T cell epitope mapping reveals immunodominance of evolutionarily conserved regions within SARS-CoV-2 proteome.

As SARS-CoV-2 variants continue to emerge capable of evading neutralizing antibodies, it has become increasingly important to fully understand the breadth and functional profile of T cell responses to determine their impact on the immune surveillance of variant strains. Here, sampling healthy individuals, we profiled the kinetics and polyfunctionality of T cell immunity elicited by mRNA vaccination. Modeling of anti-spike T cell responses against ancestral and variant strains of SARS-CoV-2 suggested that epitope immunodominance and cross-reactivity are major predictive determinants of T cell immunity.

Distinct genomic and immunologic tumor evolution in germline -driven breast cancers.

Pathogenic germline alterations cause Li-Fraumeni Syndrome (LFS), and breast cancer is the most common cancer in LFS females. We performed first of its kind multimodal analysis of LFS breast cancer (LFS-BC) compared to sporadic premenopausal BC. Nearly all LFS-BC underwent biallelic loss of with no recurrent oncogenic variants except (HER2) amplification.

Trade-offs inside the black box of neoantigen prediction.

Success of precision neoantigen-based immunotherapies hinges on the selection of immunogenic neoantigens, yet currently neither large-scale datasets nor streamlined methods are available to achieve this goal. Müller et al. present a large experimental dataset resource along with machine learning-based models to classify immunogenic neoantigens.

Identification of transcriptional programs using dense vector representations defined by mutual information with GeneVector.

Deciphering individual cell phenotypes from cell-specific transcriptional processes requires high dimensional single cell RNA sequencing. However, current dimensionality reduction methods aggregate sparse gene information across cells, without directly measuring the relationships that exist between genes. By performing dimensionality reduction with respect to gene co-expression, low-dimensional features can model these gene-specific relationships and leverage shared signal to overcome sparsity.

Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is lethal in 88% of patients, yet harbours mutation-derived T cell neoantigens that are suitable for vaccines . Here in a phase I trial of adjuvant autogene cevumeran, an individualized neoantigen vaccine based on uridine mRNA-lipoplex nanoparticles, we synthesized mRNA neoantigen vaccines in real time from surgically resected PDAC tumours. After surgery, we sequentially administered atezolizumab (an anti-PD-L1 immunotherapy), autogene cevumeran (a maximum of 20 neoantigens per patient) and a modified version of a four-drug chemotherapy regimen (mFOLFIRINOX, comprising folinic acid, fluorouracil, irinotecan and oxaliplatin).

Genomic and transcriptomic analysis of checkpoint blockade response in advanced non-small cell lung cancer.

Anti-PD-1/PD-L1 agents have transformed the treatment landscape of advanced non-small cell lung cancer (NSCLC). To expand our understanding of the molecular features underlying response to checkpoint inhibitors in NSCLC, we describe here the first joint analysis of the Stand Up To Cancer-Mark Foundation cohort, a resource of whole exome and/or RNA sequencing from 393 patients with NSCLC treated with anti-PD-(L)1 therapy, along with matched clinical response annotation. We identify a number of associations between molecular features and outcome, including (1) favorable (for example, ATM altered) and unfavorable (for example, TERT amplified) genomic subgroups, (2) a prominent association between expression of inducible components of the immunoproteasome and response and (3) a dedifferentiated tumor-intrinsic subtype with enhanced response to checkpoint blockade.

Perfecting antigen prediction.

Advances in genomics and precision measurement have continued to demonstrate the importance of the immune system across many disease types. At the heart of many emerging approaches to leverage these insights for precision immunotherapies is the computational antigen prediction problem. We propose a threefold approach to improving antigen predictions: further defining the geometry of the antigen landscape, incorporating the coupling of antigen recognition to other cellular processes, and diversifying the training sets used for models that predict immunogenicity.

Y RNAs are conserved endogenous RIG-I ligands across RNA virus infection and are targeted by HIV-1.

Pattern recognition receptors (PRRs) protect against microbial invasion by detecting specific molecular patterns found in pathogens and initiating an immune response. Although microbial-derived PRR ligands have been extensively characterized, the contribution and relevance of endogenous ligands to PRR activation remains overlooked. Here, we characterize the landscape of endogenous ligands that engage RIG-I-like receptors (RLRs) upon infection by different RNA viruses.