Biology subjects

Zanetti, M.

Publications and source records attributed to Zanetti, M..

10 recordsLinked to original sources

bioRxiv2026

Predicting Neoantigen Immunogenicity from In Vivo Immune Editing

Neoantigen immunogenicity prediction is fundamental to personalized cancer vaccines, tumor-infiltrating lymphocyte (TIL) therapy, and TCR-T cell engineering. Existing computational predictors rely primarily on in-vitro correlates of peptide presentation or models trained against assay-based reactivity, and they are typically validated within a single therapeutic setting. We reasoned that the most direct evidence of neoantigen immunogenicity is longitudinal in-vivo elimination: under immune checkpoint blockade (ICB), subclones bearing recognized neoantigens are selectively depleted over time. Here, we present the Neoantigen Elimination Model (NEMo), a two-compartment (CD8 and CD4) machine learning classifier trained on the in-vivo editing (IVE) of neoantigens across serially sequenced, ICB-treated tumors. By using mechanistically inspired NeoPrecis features designed to capture determinants of immunogenicity beyond MHC binding affinity, NEMo recovered assay-confirmed immunogenic neoantigens across four independent, unseen clinical settings -- pre-existing immunogenicity screening, personalized cancer vaccines, TIL therapy, and a radiotherapy +/- ICB ctDNA cohort -- and stratified progression-free survival more strongly than ELISPOT-confirmed reactivity. The editing signal further revealed an immune-evasion architecture in which oncogenic drivers and neoantigens restricted to lost or silenced HLA alleles are systematically spared from editing.

cancer biology↗

bioRxiv2025

NeoPrecis: Enhancing Immunotherapy Response Prediction through Integration of Qualified Immunogenicity and Clonality-Aware Neoantigen Landscapes

Despite the transformative impact of cancer immunotherapy, the need for improved patient stratification remains critical due to suboptimal response rates. While neoantigens are central to anti-tumor immunity, current metrics like tumor mutation burden are limited by their neglect of immunogenicity and tumor heterogeneity. We present NeoPrecis, a computational framework designed to refine neoantigen characterization across MHC-I and MHC-II pathways and integrate tumor clonality to improve immunotherapy response prediction. NeoPrecis features an interpretable T-cell recognition model that reveals the critical influence of MHC molecules on TCR recognition beyond mere antigen presentation. Benefit HLA alleles identified through model-driven contribution analysis exhibit significant predictive power for patient outcomes in immune checkpoint inhibitor treatment (melanoma: p-value = 0.04; NSCLC: p-value = 0.01). Applying NeoPrecis to immunotherapy-treated tumors, we show the clonality-aware neoantigen landscape improves response prediction in melanoma and heterogeneous NSCLC, achieving 11% and 20% improvement of AUROC compared to TMB respectively. Heterogeneous NSCLCs, more common among never smokers, retain more subclonal neoantigens due to lower immunoediting pressure, where NeoPrecis better captures the varying prevalence of neoantigens. We propose NeoPrecis as a more comprehensive evaluative framework for neoantigen assessment by incorporating both immunogenicity and tumor clonality, offering insights into the link between collective quality of neoantigen landscapes and immunotherapy response.

bioinformatics↗

bioRxiv2021

Immunogenic potential of neopeptides depends on parent protein subcellular location

Antigen presentation via the major histocompatibility complex (MHC) is essential for anti-tumor immunity, however the rules that determine what tumor-derived peptides will be immunogenic are still incompletely understood. Here we investigate whether protein subcellular location driven constraints on accessibility of peptides to the MHC associate with potential for peptide immunogenicity. Analyzing over 380,000 peptides from studies of MHC presentation and peptide immunogenicity, we find clear spatial biases in both eluted and immunogenic peptides. We find that including parent protein location improves prediction of peptide immunogenicity in multiple datasets. In human immunotherapy cohorts, location was associated with response to a neoantigen vaccine, and immune checkpoint blockade responders generally had a higher burden of neopeptides from accessible locations. We conclude that protein subcellular location adds important information for optimizing immunotherapies. HighlightsO_LIPeptides eluted from class I and II MHC reflect biases in the subcellular location of the parent proteins C_LIO_LIAn embedding-based indicator of parent protein location improves prediction of neoepitope immunogenicity and immunotherapy response C_LIO_LINeoepitope location improves estimation of effective neoantigen burden and stratification of potential for immunotherapy response C_LI

bioinformatics↗

bioRxiv2021

Structure selected RBM immunogens prime polyclonal memory responses that neutralize SARS-CoV-2 variants of concern

Successful control of the COVID-19 pandemic depends on vaccines that prevent transmission. The full-length Spike protein is highly immunogenic but the majority of antibodies do not target the virus: ACE2 interface. In an effort to concentrate the antibody response to the receptor-binding motif (RBM) we generated a series of conformationally-constrained immunogens by inserting solvent-exposed RBM amino acid residues into hypervariable loops of an immunoglobulin molecule. Priming C57BL/6 mice with plasmid (p)DNA encoding these constructs yielded a rapid memory response to booster immunization with recombinant Spike protein. Immune sera antibodies bound strongly to the purified receptor-binding domain (RBD) and Spike proteins. pDNA primed for a consistent response with antibodies efficient at neutralizing authentic WA1 virus and two variants of concern (VOC), B.1.351 and B.1.617.2. These findings demonstrate that immunogens built on structure selection can focus the response to conserved sites of vulnerability shared between wildtype virus and VOCs and induce neutralizing antibodies across variants.

immunology↗

bioRxiv2021

Autoimmune Alleles at the Major Histocompatibility Locus Modify Melanoma Susceptibility

Autoimmunity and cancer represent two different aspects of immune dysfunction. Autoimmunity is characterized by breakdowns in immune self-tolerance, while impaired immune surveillance can allow for tumorigenesis. The class I major histocompatibility complex (MHC-I), which displays derivatives of the cellular peptidome for immune surveillance by CD8+ T cells, serves as a common genetic link between these conditions. As melanoma-specific CD8+ T-cells have been shown to target melanocyte-specific peptide antigens more often than melanoma-specific antigens, we investigated whether vitiligo and psoriasis predisposing MHC-I alleles conferred a melanoma protective effect. In individuals with cutaneous melanoma from both The Cancer Genome Atlas (N = 451) and an independent validation cohort (N = 586), MHC-I autoimmune allele carrier status was significantly associated with a later age of melanoma diagnosis. Furthermore, MHC-I autoimmune allele carriers were significantly associated with decreased risk of developing melanoma in the Million Veterans Program cohort (OR = 0.962, p = 0.024). Existing melanoma polygenic risk scores (PRS) did not predict autoimmune allele carrier status, suggesting these alleles provide new risk-relevant information. Mechanisms of autoimmune protection were neither associated with improved melanoma-driver mutation association nor improved gene-level conserved antigen presentation relative to common alleles (population frequency > 1%). However, autoimmune alleles showed higher affinity relative to common alleles for particular windows of melanocyte conserved antigens suggesting a potential relationship between antigen processing, binding, and cell-surface presentation. Overall, this study presents evidence that MHC-I autoimmune risk alleles modulate melanoma risk unaccounted for by current PRS.

cancer biology↗

bioRxiv2021

Germline variants that influence the tumor immune microenvironment also drive response to immunotherapy

With the continued promise of immunotherapy as an avenue for treating cancer, understanding how host genetics contributes to the tumor immune microenvironment (TIME) is essential to tailoring cancer screening and treatment strategies. Approaches that intersect SNP modifiers of molecular phenotype, such as gene expression, with disease phenotypes have shown promise for implicating causal genetic factors. Here we evaluated 194 literature-curated TIME associations and 890 associations detected with 157 immune phenotype (IP) components found using genotypes from over 8,000 individuals in The Cancer Genome Atlas. Of these 1084, 233 associations comprising 219 unique TIME-SNPs were also cancer relevant, associating with cancer risk, survival, and/or immunotherapy treatment response. Many cancer relevant TIME-SNPS overlapped regions of active transcription, and were associated with gene expression in specific immune cell subsets, such as macrophages and dendritic cells. TIME-SNPs associated with cancer risk and response to immunotherapy implicated genes involved in antigen presentation, especially by antigen presenting cells. The strongest associations with survival were with PD-L1 and CTLA-4, suggesting that SNPs modifying the potential for immune evasion could contribute to disease progression. To assess whether our approach could reveal novel cancer immunotherapy targets, we inhibited CTSS, a gene implicated by cancer risk and immunotherapy response-associated TIME-SNPs; CTSS inhibition resulted in slowed tumor growth and extended survival in vivo. These results validate the potential of cancer relevant TIME-SNPs to implicate target genes for countering immune suppressive characteristics of the TIME and set the stage for future host genetics analysis integrating germline variation and TIME characteristics. SignificanceA systematic screen for common germline variants associated with the tumor immune microenvironment across > 8000 tumors reveals novel cancer risk factors and targets for immunotherapy.

cancer biology↗

bioRxiv2021

Potential global impact of the N501Y mutation on MHC-II presentation and immune escape

The B.1.1.7 SARS-CoV-2 variant, characterized by the N501Y mutation, is rapidly emerging, raising concerns about its effectiveness on natural as well as vaccine-induced adaptive viral immunity at the population level. Since CD4 T cell responses are of critical importance to the antibody response, we examined the global effects of N501Y mutation on MHC-II presentation compared to the N501 wildtype and found poorer presentation across the majority of MHC-II alleles. This suggests that the N501Y mutation may not only diminish binding of antibodies to the RBD but also interfere with their production by weakening the cooperation between T and B cells, facilitating immune escape.

bioinformatics↗

bioRxiv2020

MHC-II constrains the natural neutralizing antibody response to the SARS-CoV-2 spike RBM in humans

SARS-CoV-2 antibodies develop within two weeks of infection, but wane relatively rapidly post-infection, raising concerns about whether antibody responses will provide protection upon re-exposure. Here we revisit T-B cooperation as a prerequisite for effective and durable neutralizing antibody responses centered on a mutationally constrained RBM B cell epitope. T-B cooperation requires co-processing of B and T cell epitopes by the same B cell and is subject to MHC-II restriction. We evaluated MHC-II constraints relevant to the neutralizing antibody response to a mutationally-constrained B cell epitope in the receptor binding motif (RBM) of the spike protein. Examining common MHC-II alleles, we found that peptides surrounding this key B cell epitope are predicted to bind poorly, suggesting a lack MHC-II support in T-B cooperation, impacting generation of high-potency neutralizing antibodies in the general population. Additionally, we found that multiple microbial peptides had potential for RBM cross-reactivity, supporting previous exposures as a possible source of T cell memory. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=193 SRC="FIGDIR/small/424449v1_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@d332ccorg.highwire.dtl.DTLVardef@1ac1a95org.highwire.dtl.DTLVardef@5688dorg.highwire.dtl.DTLVardef@1133d83_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2020

The unfolded protein response links tumor aneuploidy to local immune dysregulation

Aneuploidy is a chromosomal abnormality associated with poor prognosis in many cancer types. Here we tested the hypothesis that the unfolded protein response (UPR) links mechanistically aneuploidy and local immune dysregulation. Using a single somatic copy-number alteration (SCNA) score inclusive of whole-chromosome, arm and focal chromosome alterations in a pan-cancer analysis of 9,375 samples in The Cancer Genome Atlas (TCGA) database, we found an inverse correlation with a cytotoxicity (CYT) score across disease stages. Co-expression patterns of UPR genes changed substantially between SCNAlow and SCNAhigh groups. Pathway activity scores showed increased activity by multiple branches of the UPR in response to aneuploidy. The PERK branch showed the strongest association with a reduced CYT score. The conditioned medium of aneuploid cells transmitted XBP1 splicing and caused IL-6 and Arginase1 transcription in receiver bone marrow-derived macrophages. We propose the UPR as a mechanistic link between aneuploidy and immune dysregulation in the tumor microenvironment. Statement of SignificanceAneuploidy accumulates over the life of a tumor and is associated with poor prognosis. Tumor progression is also associated with a progressive immune dysregulation. To explain these complex and concurrent disorders we tested the hypothesis that the unfolded protein could represent the link between aneuploidy and a dysregulation of local immunity favoring tumor progression.

cancer biology↗

bioRxiv2020

IRE1? regulates macrophage polarization, PD-L1 expression and tumor survival

In the tumor microenvironment local immune dysregulation is driven in part by macrophages and dendritic cells that are polarized to a mixed proinflammatory/immune suppressive phenotype. The unfolded protein response (UPR) is emerging as the possible origin of these events. Here we report that the inositol-requiring enzyme 1 (IRE1) branch of the UPR is directly involved in the polarization of macrophages in vitro and in vivo, including the upregulation of IL-6, IL-23, Arginase1, as well as surface expression of CD86 and PD-L1. Macrophages in which the IRE1/Xbp1 axis is blocked pharmacologically or deleted genetically have significantly reduced polarization, and CD86 and PD-L1 expression, which was induced independent of IFN{gamma} signaling suggesting a novel mechanism in PD-L1 regulation in macrophages. Mice with IRE1- but not Xbp1-deficient macrophages showed greater survival than controls when implanted with B16.F10 melanoma cells. Remarkably, we found a significant association between the IRE1 gene signature and CD274 gene expression in tumor-infiltrating macrophages in humans. RNASeq analysis showed that bone marrow derived macrophages with IRE1 deletion lose the integrity of the gene connectivity characteristic of regulated IRE1-dependent decay (RIDD) and the ability to activate CD274 gene expression. Thus, the IRE1/Xbp1 axis drives the polarization of macrophages in the tumor microenvironment initiating a complex immune dysregulation leading to failure of local immune surveillance.

cancer biology↗