ArticleNature immunology2024
Immunotherapy response induces divergent tertiary lymphoid structure morphologies in hepatocellular carcinoma.
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Article in Nature immunology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 85 papers, 1 of them a synthesis that pooled it.
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85citing papers in PubMed, 1 pooled it
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What it found
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
85 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Pooled it
- Neoadjuvant chemoimmunotherapy with afatinib for locally advanced head and neck squamous cell carcinoma (neoCHANCE-2): an open-label, single-arm, phase 2 study.Journal for immunotherapy of cancer · 2026Trial
- Decoding B-cell Signatures of Complete Pathologic Response to Perioperative Chemoimmunotherapy in Non-Small Cell Lung Cancer.Clinical cancer research : an official journal of the American Association for Cancer Research · 2026Trial
- Neoadjuvant tislelizumab with afatinib for locally advanced head and neck squamous cell carcinoma (neoCHANCE-1): a phase 2 clinical trial.Nature communications · 2025Trial
- Molecular biomarkers for diagnosis, prognosis, precision therapy, and immunotherapy in cholangiocarcinoma, cHCC-CCA, and HCC.Hepatology communications · 2026Review
- CD8⁺ T Cell infiltration and spatial organization in cancer: mechanisms, barriers, and therapeutic strategies.Molecular biomedicine · 2026Review
- Review
- Review
- The spatial architecture of tumor immunity: Emerging predictive biomarkers across cancer.Immunologic research · 2026Review
- Spatiotemporal mapping of tertiary lymphoid structure heterogeneity shapes immune niches and clinical outcomes in intrahepatic cholangiocarcinoma.Science advances · 2026Article
- scXpand: Pan-cancer detection of T cell clonal expansion from single-cell RNA sequencing without paired single-cell TCR sequencing.Cell genomics · 2026Article
- Tertiary lymphoid structures in cancer: their development, composition, clinical prognosis, and the drivers of the anti-tumor responses.Molecular biomedicine · 2026Review
- Review
- Strategic driving of the cancer-immunity cycle in HCC: roles of immune, molecular-targeted, and locoregional therapies.Journal of liver cancer · 2026Article
- Pulsed Electric Field Ablation Reprograms Tumor Immunity and Stimulates Germinal Center Formation in Tertiary Lymphoid Structures in Patients with Non-Small Cell Lung Cancer.Clinical cancer research : an official journal of the American Association for Cancer Research · 2026Article
- Single-Dose TACE-Like Injection of Sustained-Release Panobinostat/IL-12 Polymeric Microparticles is Effective in Preclinical Liver Cancer Models.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Review
- Review
- Beyond TLS Presence: A Functional Framework Integrating Maturity, Location, and Immune Context.Cancers · 2026Review
- Tertiary lymphoid structures in neuroinflammation coordinate neuroimmune homeostasis and pathological progression.Journal of neuroinflammation · 2026Review
25 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
39 authors.
Daniel H ShuMarlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland, Baltimore, MD, USA.
Won Jin HoDepartment of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Johns Hopkins University, Baltimore, MD, USA.ORCID http://orcid.org/0000-0003-2644-5086
Luciane T KagoharaDepartment of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Johns Hopkins University, Baltimore, MD, USA.ORCID http://orcid.org/0000-0003-1706-0950
Alexander GirgisDepartment of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Johns Hopkins University, Baltimore, MD, USA.ORCID http://orcid.org/0000-0002-4706-5480
Sarah M ShinDepartment of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
Ludmila DanilovaDepartment of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Johns Hopkins University, Baltimore, MD, USA.ORCID http://orcid.org/0000-0003-2813-3094
Jae W LeeDepartment of Pathology, Johns Hopkins University School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
Dimitrios N SidiropoulosDepartment of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Johns Hopkins University, Baltimore, MD, USA.ORCID http://orcid.org/0000-0001-5716-3917
Sarah MitchellDepartment of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
Kabeer MunjalDepartment of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
Kathryn HoweDepartment of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
Kayla J BendinelliDepartment of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Johns Hopkins University, Baltimore, MD, USA.ORCID http://orcid.org/0000-0002-4072-9002
Emma KartaliaDepartment of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
Hanfei QiDepartment of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Johns Hopkins University, Baltimore, MD, USA.ORCID http://orcid.org/0000-0002-0072-5752
Guanglan MoDepartment of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
Janelle MontagneDepartment of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
James M LeathermanDepartment of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
Tamara Y Lopez-VidalDepartment of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
Qingfeng ZhuConvergence Institute, Johns Hopkins University, Baltimore, MD, USA.ORCID http://orcid.org/0000-0001-7871-3359
Amanda L HuffDepartment of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
Xuan YuanDepartment of Biomedical Engineering, Johns Hopkins University School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
Alexei HernandezDepartment of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Johns Hopkins University, Baltimore, MD, USA.ORCID http://orcid.org/0000-0002-6044-2631
Erin M CoyneDepartment of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Johns Hopkins University, Baltimore, MD, USA.ORCID http://orcid.org/0000-0002-0393-6600
Neeha ZaidiDepartment of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Johns Hopkins University, Baltimore, MD, USA.ORCID http://orcid.org/0000-0002-0094-0049
Daniel J ZabranskyDepartment of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Johns Hopkins University, Baltimore, MD, USA.ORCID http://orcid.org/0000-0002-8184-3346
Logan L EngleDepartment of Dermatology, Johns Hopkins University School of Medicine, Johns Hopkins University, Baltimore, MD, USA.ORCID http://orcid.org/0000-0002-6375-9060
Aleksandra OgurtsovaDepartment of Dermatology, Johns Hopkins University School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
Marina BarettiDepartment of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
Daniel LaheruDepartment of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
Jennifer N DurhamDepartment of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
Hao WangDepartment of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
Joel C SunshineDepartment of Biomedical Engineering, Johns Hopkins University School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
Robert J JohnstonGenentech Inc, South San Francisco, CA, USA.
Julie Stein DeutschDepartment of Dermatology, Johns Hopkins University School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
Janis M TaubeDepartment of Dermatology, Johns Hopkins University School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
Robert A AndersConvergence Institute, Johns Hopkins University, Baltimore, MD, USA.ORCID http://orcid.org/0000-0002-2363-9072
Elizabeth M JaffeeDepartment of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Johns Hopkins University, Baltimore, MD, USA.ORCID http://orcid.org/0000-0003-3841-6549
Elana J FertigDepartment of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Johns Hopkins University, Baltimore, MD, USA. ejfertig@jhmi.edu.ORCID http://orcid.org/0000-0003-3204-342X
Mark YarchoanDepartment of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Johns Hopkins University, Baltimore, MD, USA. mark.yarchoan@jhmi.edu.ORCID http://orcid.org/0000-0003-4401-0748
Funding
Tumor Antigens for Individual Signatures and TherapyP50CA062924 · NCI · JOHNS HOPKINS UNIVERSITY · PI VOGELSTEIN, BERT · 1993 to 2022
$54.6MBiochemistry, Cellular and Molecular Biology Program: JHU BioGREAT (Biomedical Graduate REsiliency & Adaptability Training)T32GM144272 · NIGMS · JOHNS HOPKINS UNIVERSITY · PI Takanari Inoue · 2022 to 2026
$5.4MIntegrating bioinformatics into multiscale models for hepatocellular carcinomaU01CA212007 · NCI · JOHNS HOPKINS UNIVERSITY · PI EWALD, ANDREW JOSEF, FERTIG, ELANA · 2018 to 2022
$3.2MNeoadjuvant Immunotherapy Platform Study Reveals Mechanisms of Response in Hepatocellular Carcinoma (HCC)R01CA285544 · NCI · JOHNS HOPKINS UNIVERSITY · PI Won Jin Ho, Mark Yarchoan · 2024 to 2026
$2.0MMutant KRAS targeted vaccines for the interception of pancreatic cancer developmentR37CA292056 · NCI · JOHNS HOPKINS UNIVERSITY · PI Neeha Zaidi · 2024 to 2026
$2.0MSingle-cell and imaging data integration software to spatially resolve the tumor microenvironmentU01CA253403 · NCI · JOHNS HOPKINS UNIVERSITY · PI FERTIG, ELANA · 2020 to 2022
$1.2MNeoantigen-Targeted Vaccines in Combination with Immune Checkpoint Inhibitors for Pancreatic CancerK08CA248624 · NCI · JOHNS HOPKINS UNIVERSITY · PI ZAIDI, NEEHA · 2021 to 2025
$1.1MComprehensive Analysis and Multi-Omics Data Integration for Cancer-Related StudiesR50CA243627 · NCI · JOHNS HOPKINS UNIVERSITY · PI Ludmila Danilova · 2019 to 2026
$975kMass Cytometer CyTOF XT for Single-Cell BiologyS10OD034407 · OD · JOHNS HOPKINS UNIVERSITY · PI HO, WON JIN · 2024 to 2024
$499kFoundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.) U01CA212007NCI NIH HHS K08 CA248624NCI NIH HHS P50 CA062924NCI NIH HHS R01 CA285544NCI NIH HHS R37 CA292056NCI NIH HHS R50 CA243627NCI NIH HHS U01 CA212007NCI NIH HHS U01 CA253403NIGMS NIH HHS T32 GM144272NIH HHS S10 OD034407U.S. Department of Health & Human Services | National Institutes of Health (NIH) U01CA253403
Abstract
Tertiary lymphoid structures (TLS) are associated with improved response in solid tumors treated with immune checkpoint blockade, but understanding of the prognostic and predictive value of TLS and the circumstances of their resolution is incomplete. Here we show that in hepatocellular carcinoma treated with neoadjuvant immunotherapy, high intratumoral TLS density at the time of surgery is associated with pathologic response and improved relapse-free survival. In areas of tumor regression, we identify a noncanonical involuted morphology of TLS marked by dispersion of the B cell follicle, persistence of a T cell zone enriched for T cell-mature dendritic cell interactions and increased expression of T cell memory markers. Collectively, these data suggest that TLS can serve as both a prognostic and predictive marker of response to immunotherapy in hepatocellular carcinoma and that late-stage TLS may support T cell memory formation after elimination of a viable tumor.
Indexed as
Carcinoma, HepatocellularImmunotherapyLiver NeoplasmsTertiary Lymphoid StructuresAgedDendritic CellsFemaleHumansImmune Checkpoint InhibitorsImmunologic MemoryLymphocytes, Tumor-InfiltratingMaleMiddle AgedNeoadjuvant TherapyPrognosisImmune Checkpoint Inhibitors
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