Evidence map›Paper›PMID 36068918›Full record

ArticleMolecular therapy : the journal of the American Society of Gene Therapy2023

Inducing mismatch repair deficiency sensitizes immune-cold neuroblastoma to anti-CTLA4 and generates broad anti-tumor immune memory.

Mikal El-Hajjar, Lara Gerhardt, Megan M Y Hong, Mithunah Krishnamoorthy, Rene Figueredo, Xiufen Zheng, James Koropatnick, Saman Maleki Vareki

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

Article in Molecular therapy : the journal of the American Society of Gene Therapy, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.

0numbers the graph read from it
0cells of the map it votes in
11citing papers in PubMed
1.1field-weighted citation impact, top 21% 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

11 citing papers in PubMed, 12 citations in OpenAlex.

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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

8 authors at 1 institution in 1 country.

Mikal El-HajjarDepartment of Microbiology and Immunology, Western University, London, ON, Canada; London Regional Cancer Program, Lawson Health Research Institute, London, ON, Canada.
Lara GerhardtDepartment of Pathology and Laboratory Medicine, Western University, London, ON, Canada.
Megan M Y HongDepartment of Pathology and Laboratory Medicine, Western University, London, ON, Canada.
Mithunah KrishnamoorthyDepartment of Pathology and Laboratory Medicine, Western University, London, ON, Canada.
Rene FigueredoDepartment of Oncology, Western University, London, ON, Canada.
Xiufen ZhengDepartment of Microbiology and Immunology, Western University, London, ON, Canada; Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada; Department of Oncology, Western University, London, ON, Canada; Department of Surgery, Western University, London, ON, Canada.
James KoropatnickDepartment of Microbiology and Immunology, Western University, London, ON, Canada; Department of Oncology, Western University, London, ON, Canada; London Regional Cancer Program, Lawson Health Research Institute, London, ON, Canada.
Saman Maleki VarekiDepartment of Pathology and Laboratory Medicine, Western University, London, ON, Canada; Department of Oncology, Western University, London, ON, Canada; London Regional Cancer Program, Lawson Health Research Institute, London, ON, Canada. Electronic address: saman.malekivareki@lhsc.on.ca.
Western University · CA

Funding

CIHR MOP#389137
6 · The paper itself

Abstract

Immune checkpoint blockade can induce potent and durable responses in patients with highly immunogenic mismatch repair-deficient tumors; however, these drugs are ineffective against immune-cold neuroblastoma tumors. To establish a role for a T cell-based therapy against neuroblastoma, we show that T cell and memory T cell-dependent gene expression are associated with improved survival in high-risk neuroblastoma patients. To stimulate anti-tumor immunity and reproduce this immune phenotype in neuroblastoma tumors, we used CRISPR-Cas9 to knockout MLH1-a crucial molecule in the DNA mismatch repair pathway-to induce mismatch repair deficiency in a poorly immunogenic murine neuroblastoma model. Induced mismatch repair deficiency increased the expression of proinflammatory genes and stimulated T cell infiltration into neuroblastoma tumors. In contrast to adult cancers with induced mismatch repair deficiency, neuroblastoma tumors remained unresponsive to anti-PD1 treatment. However, anti-CTLA4 therapy was highly effective against these tumors. Anti-CTLA4 therapy promoted immune memory and T cell epitope spreading in cured animals. Mechanistically, the effect of anti-CTLA4 therapy against neuroblastoma tumors with induced mismatch repair deficiency is CD4

Indexed as

Brain NeoplasmsColorectal NeoplasmsNeuroblastomaAnimalsImmunologic MemoryMiceNeoplastic Syndromes, Hereditaryanti-CTLA4anti-PD1anti-tumor immunityimmune checkpoint blockadeimmunological memoryMMR deficiencyneuroblastomaT cells

Identifiers

PMID36068918
PMCPMC9931548
OpenAlexW4294676455

What OpenQuestion holds

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LicenceCC BY
Read underepoch 390

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.