Evidence map›Paper›PMID 40050047›Full record

ArticleJournal for immunotherapy of cancer2025

Identification of a conserved subset of cold tumors responsive to immune checkpoint blockade.

Jade Moore, Jim Gkantalis, Ines Guix, William Chou, Kobe Yuen, Ann A Lazar, Matthew Spitzer, Alexis Combes, Mary Helen Barcellos-Hoff

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Journal for immunotherapy of cancer, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.

0numbers the graph read from it
0cells of the map it votes in
7citing papers in PubMed
–field-weighted citation impact
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

7 citing papers in PubMed.

  1. Review
  2. Identifying a Csmd3Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026
    Article
  3. Article
  4. Review
  5. Review
  6. Review
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4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

9 authors.

Jade MooreDepartment of Radiation Oncology, University of California San Francisco, San Francisco, California, USA.
Jim GkantalisDepartment of Radiation Oncology, University of California San Francisco, San Francisco, California, USA.
Ines GuixDepartment of Radiation Oncology, University of California San Francisco, San Francisco, California, USA.
William ChouDepartment of Radiation Oncology, University of California San Francisco, San Francisco, California, USA.
Kobe YuenOncology Biomarker Development, Genentech, South San Francisco, California, USA.
Ann A LazarDivision of Oral Epidemiology and Division of Biostatistics, University of California San Francisco, San Francisco, California, USA.
Matthew SpitzerDepts of Otolaryngology-Head and Neck Surgery and of Microbiology and Immunology, University of California San Francisco, San Francisco, California, USA.
Alexis CombesDepartment of Pathology, University of California San Francisco, San Francisco, California, USA.
Mary Helen Barcellos-HoffDepartment of Radiation Oncology, University of California San Francisco, San Francisco, California, USA MaryHelen.Barcellos-Hoff@ucsf.edu.ORCID http://orcid.org/0000-0002-5994-9558

Funding

Translational InformaticsP30CA082103 · NCI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI Alan Ashworth · 1999 to 2026
$209.7M
Molecular and Cellular Mechanisms in CancerT32CA108462 · NCI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI GOGA, ANDREI · 2004 to 2024
$10.4M
Contribution of development and age to breast cancer etiologyR01CA190980 · NCI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI BARCELLOS-HOFF, MARY HELEN · 2015 to 2020
$2.6M
Definition of Immune Infiltrate Phenotype and DNA Damage Response Deficits Across Diverse Murine Mammary CarcinomasR01CA239235 · NCI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI BARCELLOS-HOFF, MARY HELEN · 2019 to 2023
$2.5M
Investigating the Genesis of Tumor Immune Microenvironment (TIME) as a function of InflammationR01CA270332 · NCI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI Mary Helen Barcellos-Hoff · 2023 to 2026
$2.2M
UCSF DVS CyTOF Mass CytometerS10OD018040 · OD · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI LANIER, LEWIS LEE · 2014 to 2014
$600k
NCI NIH HHS P30 CA082103NCI NIH HHS R01 CA190980NCI NIH HHS R01 CA239235NCI NIH HHS R01 CA270332NCI NIH HHS T32 CA108462NIH HHS S10 OD018040
6 · The paper itself

Abstract

backgroundThe efficacy of immune checkpoint blockade (ICB) depends on restoring immune recognition of cancer cells that have evaded immune surveillance. Transforming growth factor-beta (TGFβ) is associated with immune-poor, so-called cold tumors whereas loss of its signaling promotes DNA misrepair that could stimulate immune response.

methodsWe analyzed transcriptomic data from IMvigor210, The Cancer Genome Atlas, and Tumor Immune Syngeneic MOuse data sets to evaluate the predictive value of high βAlt, a score representing low expression of a signature consisting of TGFβ targets and high expression of genes involved in error-prone DNA repair. The immune context of βAlt was assessed by evaluating tumor-educated immune signatures. An ICB-resistant, high βAlt preclinical tumor model was treated with a TGFβ inhibitor, radiation, and/or ICB and assessed for immune composition and tumor control.

resultsWe found that a high βAlt score predicts ICB response yet is paradoxically associated with an immune-poor tumor microenvironmentcancer in both human and mouse tumors. We postulated that high βAlt cancers consist of cancer cells in which loss of TGFβ signaling generates a TGFβ rich, immunosuppressive tumor microenvironment. Accordingly, preclinical modeling showed that TGFβ inhibition followed by radiotherapy could convert an immune-poor, high βAlt tumor to an immune-rich, ICB-responsive tumor. Mechanistically, TGFβ inhibition increased activated natural killer (NK) cells, which were required to recruit lymphocytes to respond to ICB in irradiated tumors. NK cell activation signatures were also increased in high βAlt, cold mouse and human tumors that responded to ICB.

conclusionsThese studies indicate that loss of TGFβ signaling competency and gain of error-prone DNA repair identifies a subset of cold tumors that are responsive to ICB. Our mechanistic studies show that inhibiting TGFβ activity can convert a high βAlt, cold tumor into ICB-responsive tumors via NK cells. A biomarker consisting of combined TGFβ, DNA repair, and immune context signatures is a means to prospectively identify patients whose cancers may be converted from cold to hot with appropriate therapy.

Indexed as

Immune Checkpoint InhibitorsNeoplasmsAnimalsHumansMiceTransforming Growth Factor betaTumor MicroenvironmentImmune Checkpoint InhibitorsTransforming Growth Factor betaBiomarkerCytokineRadiotherapy/radioimmunotherapyTumor microenvironment - TME

Identifiers

PMID40050047
PMCPMC11887281

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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.