Evidence map›Paper›PMID 34021032›Full record

ArticleJournal for immunotherapy of cancer2021

Pathways of immune exclusion in metastatic osteosarcoma are associated with inferior patient outcomes.

John A Ligon, Woonyoung Choi, Gady Cojocaru, Wei Fu, Emily Han-Chung Hsiue, Teniola F Oke, Nicholas Siegel, Megan H Fong, Brian Ladle, Christine A Pratilas and 13 more

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Journal for immunotherapy of cancer, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 83 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
83citing papers in PubMed, 1 pooled it
7.2field-weighted citation impact, top 2% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

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.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

83 citing papers in PubMed, 1 synthesis or guideline pooled it, 116 citations in OpenAlex.

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23 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

23 authors at 1 institution in 1 country.

John A LigonDepartment of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.ORCID 0000-0001-5513-1233
Woonyoung ChoiGreenberg Bladder Cancer Institute and Brady Urological Institute, Johns Hopkins University, Baltimore, Maryland, USA.
Gady CojocaruGreenberg Bladder Cancer Institute and Brady Urological Institute, Johns Hopkins University, Baltimore, Maryland, USA.
Wei FuDepartment of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Emily Han-Chung HsiueCellular and Molecular Medicine Program, Johns Hopkins University, Baltimore, Maryland, USA.
Teniola F OkeDepartment of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Nicholas SiegelDepartment of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Megan H FongGreenberg Bladder Cancer Institute and Brady Urological Institute, Johns Hopkins University, Baltimore, Maryland, USA.ORCID 0000-0002-6463-1237
Brian LadleDepartment of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Christine A PratilasDepartment of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Carol D MorrisDivision of Orthopaedic Oncology, Department of Orthopaedic Surgery, Johns Hopkins University, Baltimore, Maryland, USA.
Adam LevinDivision of Orthopaedic Oncology, Department of Orthopaedic Surgery, Johns Hopkins University, Baltimore, Maryland, USA.
Daniel S RheeSurgery, Johns Hopkins University, Baltimore, Maryland, USA.
Christian F MeyerDepartment of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Ada J TamDepartment of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Richard BlosserDepartment of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Elizabeth D ThompsonPathology, Johns Hopkins University, Baltimore, Maryland, USA.
Aditya SuruDepartment of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
David McConkeyGreenberg Bladder Cancer Institute and Brady Urological Institute, Johns Hopkins University, Baltimore, Maryland, USA.
Franck HousseauDepartment of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Robert AndersPathology, Johns Hopkins University, Baltimore, Maryland, USA.
Drew M PardollDepartment of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Nicolas LlosaDepartment of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA nllosa1@jhmi.edu.ORCID 0000-0001-7047-0858
Johns Hopkins University · US

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

backgroundCurrent therapy for osteosarcoma pulmonary metastases (PMs) is ineffective. The mechanisms that prevent successful immunotherapy in osteosarcoma are incompletely understood. We investigated the tumor microenvironment of metastatic osteosarcoma with the goal of harnessing the immune system as a therapeutic strategy.

methods66 osteosarcoma tissue specimens were analyzed by immunohistochemistry (IHC) and immune markers were digitally quantified. Tumor-infiltrating lymphocytes (TILs) from 25 specimens were profiled by functional cytometry. Comparative transcriptomic studies of distinct tumor-normal lung 'PM interface' and 'PM interior' regions from 16 PMs were performed. Clinical follow-up (median 24 months) was available from resection.

resultsIHC revealed a statistically significantly higher concentration of TILs expressing immune checkpoint and immunoregulatory molecules in PMs compared with primary bone tumors (including programmed cell death 1 (PD-1), programmed death ligand 1 (PD-L1), lymphocyte-activation gene 3 (LAG-3), T-cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), and indoleamine 2,3-dioxygenase (IDO1). Remarkably, these lymphocytes are excluded at the PM interface compared with PM interior. TILs from PMs exhibited significantly higher amounts of PD-1 and LAG-3 and functional cytokines including interferon-γ (IFNγ) by flow cytometry. Gene expression profiling further confirmed the presence of CD8 and CD4 lymphocytes concentrated at the PM interface, along with upregulation of immunoregulatory molecules and IFNγ-driven genes in the same region. We further discovered a strong alternatively activated macrophage signature throughout the entire PMs along with a polymorphonuclear myeloid-derived suppressor cell signature focused at the PM interface. Expression of PD-L1, LAG-3, and colony-stimulating factor 1 receptor (CSF1R) at the PM interface was associated with significantly worse progression-free survival (PFS), while gene sets indicative of productive T cell immune responses (CD8 T cells, T cell survival, and major histocompatibility complex class 1 expression) were associated with significantly improved PFS.

conclusionsOsteosarcoma PMs exhibit immune exclusion characterized by the accumulation of TILs at the PM interface. These TILs produce effector cytokines, suggesting their capability of activation and recognition of tumor antigens. Our findings suggest cooperative immunosuppressive mechanisms in osteosarcoma PMs including immune checkpoint molecule expression and the presence of immunosuppressive myeloid cells. We identify cellular and molecular signatures that are associated with patient outcomes, which could be exploited for successful immunotherapy.

Indexed as

ImmunotherapyBiomarkers, TumorBone NeoplasmsCytokinesElectronic Health RecordsHumansImmune Checkpoint ProteinsLung NeoplasmsLymphocyte ActivationLymphocytes, Tumor-InfiltratingMacrophage ActivationMyeloid-Derived Suppressor CellsOsteosarcomaProgression-Free SurvivalRetrospective StudiesTranscriptomeBiomarkers, TumorCytokinesImmune Checkpoint Proteinspediatricssarcomatranslational medical researchtumor microenvironment

Identifiers

PMID34021032
PMCPMC8144029
OpenAlexW3160748480

What OpenQuestion holds

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LicenceCC BY-NC
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Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.