Evidence map›Paper›PMID 37891555›Full record

ArticleBMC cancer2023

Regulation of HHLA2 expression in kidney cancer and myeloid cells.

Tomonari Shigemura, Nahuel Perrot, Zimo Huang, Rupal S Bhatt, Aseman Bagheri Sheshdeh, Nourhan El Ahmar, Fatme Ghandour, Sabina Signoretti, David F McDermott, Gordon J Freeman and 1 more

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

Article in BMC cancer, 2023. 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
1.4field-weighted citation impact, top 17% 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

7 citing papers in PubMed, 6 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

11 authors at 3 institutions in 1 country.

Tomonari ShigemuraDepartment of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Ave., Boston, MA, 02215, USA.
Nahuel PerrotDepartment of Medicine, Division of Medical Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave, Boston, MA, 02215, USA.
Zimo HuangDepartment of Medicine, Division of Medical Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave, Boston, MA, 02215, USA.
Rupal S BhattDepartment of Medicine, Division of Medical Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave, Boston, MA, 02215, USA.
Aseman Bagheri SheshdehDepartment of Pathology, Brigham and Women's Hospital, Harvard Medical School, 75 Francis St, Boston, MA, 02115, USA.
Nourhan El AhmarDepartment of Pathology, Brigham and Women's Hospital, Harvard Medical School, 75 Francis St, Boston, MA, 02115, USA.
Fatme GhandourDepartment of Pathology, Brigham and Women's Hospital, Harvard Medical School, 75 Francis St, Boston, MA, 02115, USA.
Sabina SignorettiDepartment of Pathology, Brigham and Women's Hospital, Harvard Medical School, 75 Francis St, Boston, MA, 02115, USA.
David F McDermottDepartment of Medicine, Division of Medical Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave, Boston, MA, 02215, USA.
Gordon J FreemanDepartment of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Ave., Boston, MA, 02215, USA. gordon_freeman@dfci.harvard.edu.
Kathleen M MahoneyDepartment of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Ave., Boston, MA, 02215, USA. kmmah5@bidmc.harvard.edu.
Harvard University · USBeth Israel Deaconess Medical Center · USBrigham and Women's Hospital · US

Funding

Treating the P13-Kinase/AKTP50CA101942 · NCI · BETH ISRAEL DEACONESS MEDICAL CENTER · PI David McDermott · 2003 to 2026
$53.4M
Transgenic/KnockoutP01AI056299 · NIAID · HARVARD UNIVERSITY (MEDICAL SCHOOL) · PI BLAZAR, BRUCE R · 2003 to 2023
$42.5M
NCI NIH HHS P50 CA101942NIAID NIH HHS P01 AI056299NIH HHS P50 CA101942
6 · The paper itself

Abstract

backgroundThe immune checkpoint HERV-H LTR-associating 2 (HHLA2) is expressed in kidney cancer and various other tumor types. Therapeutics targeting HHLA2 or its inhibitory receptor KIR3DL3 are being developed for solid tumors, including renal cell carcinoma (RCC). However, the regulation of HHLA2 expression remains poorly understood. A better understanding of HHLA2 regulation in tumor cells and the tumor microenvironment is crucial for the successful translation of these therapeutic agents into clinical applications.

methodsFlow cytometry and quantitative real-time PCR were used to analyze HHLA2 expression in primary kidney tumors ex vivo and during in vitro culture. HHLA2 expression in A498 and 786-O ccRCC cell lines was examined in vitro and in subcutaneous tumor xenografts in NSG mice. Monocytes and dendritic cells were analyzed for HHLA2 expression. We tested a range of cytokines and culture conditions, including hypoxia, to induce HHLA2 expression.

resultsAnalysis of HHLA2 expression revealed that HHLA2 is expressed on tumor cells in primary kidney tumors ex vivo; however, its expression gradually diminishes during a 4-week in vitro culture period. A498 and 786-O ccRCC tumor cell lines do not express HHLA2 in vitro, but HHLA2 expression was observed when grown as subcutaneous xenografts in NSG immunodeficient mice. Induction experiments using various cytokines and culture conditions failed to induce HHLA2 expression in A498 and 786-O tumor cell lines in vitro. Analysis of HHLA2 expression in monocytes and dendritic cells demonstrated that only IL-10 and BMP4, along with IL-1β and IL-6 to a lesser extent, modestly enhanced HHLA2 protein and mRNA expression.

conclusionsHHLA2 expression is induced on kidney cancer cells in vivo by a tumor microenvironmental signal that is not present in vitro. HHLA2 expression is differentially regulated in kidney cancer epithelial cells and monocytes. Cytokines, particularly IL10, that induce HHLA2 expression in monocytes fail to upregulate HHLA2 expression in tumor cell lines in vitro. These findings underscore the importance of the interplay between tumor cell and tumor microenvironmental signals in the regulation of HHLA2. Further investigation is warranted to elucidate the mechanisms involved in HHLA2 regulation and its implications for therapeutic development.

Indexed as

Carcinoma, Renal CellEndogenous RetrovirusesKidney NeoplasmsAnimalsCytokinesHumansImmunoglobulinsMiceMyeloid CellsTumor MicroenvironmentCytokinesHHLA2 protein, humanImmunoglobulinsccRCCHHLA2Kidney cancerKIR3DL3MonocytesTumor microenvironment

Identifiers

PMID37891555
PMCPMC10605970
OpenAlexW4387996380

What OpenQuestion holds

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LicenceCC BY
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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.