Neoantigens: promising targets for cancer therapy

Signal Transduction and Targeted Therapy, Год журнала: 2023, Номер 8(1)

Опубликована: Янв. 6, 2023

Abstract Recent advances in neoantigen research have accelerated the development and regulatory approval of tumor immunotherapies, including cancer vaccines, adoptive cell therapy antibody-based therapies, especially for solid tumors. Neoantigens are newly formed antigens generated by cells as a result various tumor-specific alterations, such genomic mutation, dysregulated RNA splicing, disordered post-translational modification, integrated viral open reading frames. recognized non-self trigger an immune response that is not subject to central peripheral tolerance. The quick identification prediction neoantigens been made possible advanced next-generation sequencing bioinformatic technologies. Compared tumor-associated antigens, highly immunogenic provide emerging targets personalized serve prospective predictors survival prognosis checkpoint blockade responses. therapies will be aided understanding mechanism underlying neoantigen-induced anti-tumor streamlining process neoantigen-based immunotherapies. This review provides overview on characterization outlines clinical applications immunotherapeutic strategies based neoantigens. We also explore their current status, inherent challenges, translation potential.

Язык: Английский

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Shotgun transcriptome, spatial omics, and isothermal profiling of SARS-CoV-2 infection reveals unique host responses, viral diversification, and drug interactions

Nature Communications, Год журнала: 2021, Номер 12(1)

Опубликована: Март 12, 2021

Abstract In less than nine months, the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) killed over a million people, including >25,000 in New York City (NYC) alone. The COVID-19 pandemic caused by SARS-CoV-2 highlights clinical needs to detect infection, track strain evolution, and identify biomarkers of disease course. To address these challenges, we designed fast (30-minute) colorimetric test (LAMP) for infection from naso/oropharyngeal swabs large-scale shotgun metatranscriptomics platform (total-RNA-seq) host, viral, microbial profiling. We applied methods specimens gathered 669 patients during first two months outbreak, yielding broad molecular portrait emerging disease. find significant enrichment NYC-distinctive clade virus (20C), as well host responses interferon, ACE, hematological, olfaction pathways. addition, use 50,821 patient records that renin–angiotensin–aldosterone system inhibitors have protective effect severe outcomes, unlike similar drugs. Finally, spatial transcriptomic data autopsy tissues reveal distinct ACE2 expression loci, with macrophage neutrophil infiltration lungs. These findings can inform public health may help develop drive diagnostic, prevention, treatment strategies.

Язык: Английский

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Next-generation computational tools for interrogating cancer immunity

Nature Reviews Genetics, Год журнала: 2019, Номер 20(12), С. 724 - 746

Опубликована: Сен. 12, 2019

Язык: Английский

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Challenges in neoantigen-directed therapeutics

Cancer Cell, Год журнала: 2022, Номер 41(1), С. 15 - 40

Опубликована: Ноя. 10, 2022

Язык: Английский

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LAG-3 and PD-1 synergize on CD8+ T cells to drive T cell exhaustion and hinder autocrine IFN-γ-dependent anti-tumor immunity

Cell, Год журнала: 2024, Номер 187(16), С. 4355 - 4372.e22

Опубликована: Авг. 1, 2024

Язык: Английский

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The immunopeptidome landscape associated with T cell infiltration, inflammation and immune editing in lung cancer

Nature Cancer, Год журнала: 2023, Номер 4(5), С. 608 - 628

Опубликована: Май 1, 2023

Abstract One key barrier to improving efficacy of personalized cancer immunotherapies that are dependent on the tumor antigenic landscape remains patient stratification. Although patients with CD3 + CD8 T cell-inflamed tumors typically show better response immune checkpoint inhibitors, it is still unknown whether immunopeptidome repertoire presented in highly inflamed and noninflamed substantially different. We surveyed 61 regions adjacent nonmalignant lung tissues from 8 performed deep antigen discovery combining immunopeptidomics, genomics, bulk spatial transcriptomics, explored heterogeneous expression presentation (neo)antigens. In present study, we associated diverse cell populations found a relatively higher frequency predicted neoantigens located within HLA-I hotspots cell-excluded tumors. such recognition, supporting their involvement editing. This could have implications for choice combination therapies tailored patient’s mutanome microenvironment.

Язык: Английский

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Splicing neoantigen discovery with SNAF reveals shared targets for cancer immunotherapy

Science Translational Medicine, Год журнала: 2024, Номер 16(730)

Опубликована: Янв. 17, 2024

Immunotherapy has emerged as a crucial strategy to combat cancer by “reprogramming” patient’s own immune system. Although immunotherapy is typically reserved for patients with high mutational burden, neoantigens produced from posttranscriptional regulation may provide an untapped reservoir of common immunogenic targets new targeted therapies. To comprehensively define tumor-specific and likely patient RNA-Seq, we developed Splicing Neo Antigen Finder (SNAF), easy-to-use open-source computational workflow predict splicing-derived MHC-bound peptides (T cell antigen) unannotated transmembrane proteins altered extracellular epitopes (B antigen). This uses highly accurate deep learning immunogenicity prediction (DeepImmuno) in conjunction algorithms rank the tumor specificity (BayesTS) regulators mis-splicing (RNA-SPRINT). T antigens SNAF were frequently evidenced HLA-presented mass spectrometry (MS) response melanoma. neoantigen burden was attributed coordinated splicing factor dysregulation. Shared found up 90% melanoma, correlated overall survival multiple cohorts, induced reactivity, characterized distinct cells origin amino acid preferences. In addition neoantigens, our B focused pipeline (SNAF-B) identified class neoepitopes, which termed ExNeoEpitopes. ExNeoEpitope full-length mRNA predictions specific validated using long-read isoform sequencing vitro localization assays. Therefore, systematic identification revealed potential shared therapy heterogeneous cancers.

Язык: Английский

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Prediction of tumor-reactive T cell receptors from scRNA-seq data for personalized T cell therapy

Nature Biotechnology, Год журнала: 2024, Номер 43(1), С. 134 - 142

Опубликована: Март 7, 2024

The identification of patient-derived, tumor-reactive T cell receptors (TCRs) as a basis for personalized transgenic therapies remains time- and cost-intensive endeavor. Current approaches to identify TCRs analyze tumor mutations predict activating (neo)antigens use these either enrich infiltrating lymphocyte (TIL) cultures or validate individual autologous therapies. Here we combined high-throughput TCR cloning reactivity validation train predicTCR, machine learning classifier that identifies TILs in an antigen-agnostic manner based on single-TIL RNA sequencing. PredicTCR from diverse cancers better than previous gene set enrichment-based approaches, increasing specificity sensitivity (geometric mean) 0.38 0.74. By predicting matter days, clonotypes can be prioritized accelerate the manufacture

Язык: Английский

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Neoantigen prediction and computational perspectives towards clinical benefit: recommendations from the ESMO Precision Medicine Working Group

Annals of Oncology, Год журнала: 2020, Номер 31(8), С. 978 - 990

Опубликована: Июнь 28, 2020

Язык: Английский

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Increased risk of severe clinical course of COVID-19 in carriers of HLA-C*04:01

EClinicalMedicine, Год журнала: 2021, Номер 40, С. 101099 - 101099

Опубликована: Сен. 2, 2021

BackgroundSince the beginning of coronavirus disease 2019 (COVID-19) pandemic, there has been increasing urgency to identify pathophysiological characteristics leading severe clinical course in patients infected with acute respiratory syndrome 2 (SARS-CoV-2). Human leukocyte antigen alleles (HLA) have suggested as potential genetic host factors that affect individual immune response SARS-CoV-2. We sought evaluate this hypothesis by conducting a multicenter study using HLA sequencing.MethodsWe analyzed association between COVID-19 severity and HLAs 435 individuals from Germany (n = 135), Spain 133), Switzerland 20) United States 147), who had enrolled March 2020 August 2020. This included older than 18 years, diagnosed representing full spectrum disease. Finally, we tested our results meta-analysing data prior genome-wide studies (GWAS).FindingsWe describe HLA-C*04:01 COVID-19. Carriers twice risk intubation when SARS-CoV-2 (risk ratio 1.5 [95% CI 1.1–2.1], odds 3.5 1.9–6.6], adjusted p-value 0.0074). These findings are based on four countries corroborated independent GWAS. Our biologically plausible, fewer predicted bindings sites for relevant peptides compared other alleles.InterpretationHLA-C*04:01 carrier state is associated suggest class I role defense against SARS-CoV-2.FundingFunded Roche Sequencing Solutions, Inc.

Язык: Английский

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