Evidence map›Paper›PMID 36528023›Full record

ArticleCell metabolism2023

Microenvironmental ammonia enhances T cell exhaustion in colorectal cancer.

Hannah N Bell, Amanda K Huber, Rashi Singhal, Navyateja Korimerla, Ryan J Rebernick, Roshan Kumar, Marwa O El-Derany, Peter Sajjakulnukit, Nupur K Das, Samuel A Kerk and 16 more

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PubMed Full text at PMC Publisher
In one paragraph

Article in Cell metabolism, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 131 papers.

0numbers the graph read from it
0cells of the map it votes in
131citing papers in PubMed
13.3field-weighted citation impact, top 1% 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

131 citing papers in PubMed, 159 citations in OpenAlex.

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  9. Ammonia Detoxification Inhibits Liver Metastasis by Reshaping Hepatic Microenvironment.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026
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71 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

26 authors at 5 institutions in 3 countries.

Hannah N BellDepartment of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA.
Amanda K HuberDepartment of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA.
Rashi SinghalDepartment of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA.
Navyateja KorimerlaDepartment of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA; University of Michigan Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA.
Ryan J RebernickDepartment of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
Roshan KumarDepartment of Biological Chemistry, University of Michigan Medical School, Ann Arbor, MI, USA.
Marwa O El-DeranyDepartment of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Biochemistry, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt.
Peter SajjakulnukitDepartment of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA.
Nupur K DasDepartment of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA.
Samuel A KerkDepartment of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA.
Sumeet SolankiDepartment of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA.
Jadyn G JamesDepartment of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA.
Donghwan KimCenter for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Li ZhangDepartment of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA.
Brandon ChenDepartment of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA.
Rohit MehraDepartment of Pathology, University of Michigan, Ann Arbor, MI, USA.
Timothy L FrankelDepartment of Surgery, University of Michigan, Ann Arbor, MI, USA; Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA.
Balázs GyőrffyDepartment of Bioinformatics and 2(nd) Department of Pediatrics, Semmelweis University, Budapest, Hungary; TTK Cancer Biomarker Research Group, Institute of Enzymology, Budapest, Hungary.
Eric R FearonUniversity of Michigan Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, USA; Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA; Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA.
Marina Pasca di MaglianoDepartment of Surgery, University of Michigan, Ann Arbor, MI, USA; Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA.
Frank J GonzalezCenter for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Ruma BanerjeeDepartment of Biological Chemistry, University of Michigan Medical School, Ann Arbor, MI, USA.
Daniel R WahlDepartment of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA; University of Michigan Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA.
Costas A LyssiotisDepartment of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA; University of Michigan Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA; Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
Michael GreenDepartment of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA; University of Michigan Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA; Veteran's Affairs Ann Arbor Healthcare System, Ann Arbor, MI, USA.
Yatrik M ShahDepartment of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA; University of Michigan Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA; Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA. Electronic address: shahy@umich.edu.
University of Michigan–Ann Arbor · USAin Shams University · EGCenter for Cancer Research · USInstitute of Molecular Life Sciences · HUNational Cancer Institute · US

Funding

XenograftP30CA046592 · NCI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI Alexey I Nesvizhskii · 1988 to 2026
$178.2M
MICHIGAN MEDICAL SCIENTIST TRAINING PROGRAMT32GM007863 · NIGMS · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI COLLINS, KATHLEEN L. · 1985 to 2024
$38.3M
Xenobiotic receptorsZIABC005562 · NCI · DIVISION OF BASIC SCIENCES - NCI · PI GONZALEZ, FRANK J · 2009 to 2025
$26.9M
CELLULAR AND MOLECULAR BIOLOGY AT MICHIGANT32GM007315 · NIGMS · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI PUTHENVEEDU, MANOJKUMAR A · 1985 to 2021
$12.8M
Metabolomics CoreP01HL149633 · NHLBI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI TEWARI, MUNEESH · 2020 to 2024
$11.1M
SYTEMS AND INTEGRATIVE BIOLOGYT32GM008322 · NIGMS · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI LOW, MALCOLM JAMES · 1990 to 2020
$5.7M
Control of iron absorption by intestinal HIF2 in iron and hematological disordersR01DK095201 · NIDDK · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI SHAH, YATRIK M · 2012 to 2025
$5.7M
The role of HIF2alpha in colon carcinogenesisR01CA148828 · NCI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI SHAH, YATRIK M · 2010 to 2025
$5.2M
Sulfide Oxidation and SignalingR35GM130183 · NIGMS · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI RUMA V BANERJEE · 2019 to 2026
$3.6M
Intratumoral Metabolic Crosstalk Promotes Therapeutic Resistance in Pancreatic CancerR37CA237421 · NCI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI Costas Andreas Lyssiotis · 2020 to 2026
$2.6M
Understanding the mechanisms of iron addiction in colon cancerR01CA245546 · NCI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI SHAH, YATRIK M · 2020 to 2024
$2.3M
Stromal metabolism promotes therapeutic resistance in pancreatic cancerR01CA248160 · NCI · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI LYSSIOTIS, COSTAS ANDREAS · 2020 to 2024
$2.0M
NCI NIH HHS F30 CA257292NCI NIH HHS F31 CA247457NCI NIH HHS F99 CA264414NCI NIH HHS K08 CA234416NCI NIH HHS P30 CA046592NCI NIH HHS R01 CA148828NCI NIH HHS R01 CA244931NCI NIH HHS R01 CA245546NCI NIH HHS R01 CA248160NCI NIH HHS R37 CA237421NHLBI NIH HHS P01 HL149633NIDDK NIH HHS R01 DK095201NIGMS NIH HHS R35 GM130183NIGMS NIH HHS T32 GM007315NIGMS NIH HHS T32 GM007863NIGMS NIH HHS T32 GM008322
6 · The paper itself

Abstract

Effective therapies are lacking for patients with advanced colorectal cancer (CRC). The CRC tumor microenvironment has elevated metabolic waste products due to altered metabolism and proximity to the microbiota. The role of metabolite waste in tumor development, progression, and treatment resistance is unclear. We generated an autochthonous metastatic mouse model of CRC and used unbiased multi-omic analyses to reveal a robust accumulation of tumoral ammonia. The high ammonia levels induce T cell metabolic reprogramming, increase exhaustion, and decrease proliferation. CRC patients have increased serum ammonia, and the ammonia-related gene signature correlates with altered T cell response, adverse patient outcomes, and lack of response to immune checkpoint blockade. We demonstrate that enhancing ammonia clearance reactivates T cells, decreases tumor growth, and extends survival. Moreover, decreasing tumor-associated ammonia enhances anti-PD-L1 efficacy. These findings indicate that enhancing ammonia detoxification can reactivate T cells, highlighting a new approach to enhance the efficacy of immunotherapies.

Indexed as

AmmoniaColorectal NeoplasmsAnimalsImmunotherapyMiceT-Cell ExhaustionT-LymphocytesTumor MicroenvironmentAmmoniaammoniacancer metabolismimmunotherapytumor microenvironment

Identifiers

PMID36528023
PMCPMC9841369
OpenAlexW4311860832

What OpenQuestion holds

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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.