{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Bell HN"],"funding":["NIDDK NIH HHS","NHLBI NIH HHS","Crohn's & Colitis Foundation","NCI NIH HHS","NIGMS NIH HHS"],"pagination":["134-149.e6"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC9841369"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["35(1)"],"pubmed_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."],"journal":["Cell metabolism"],"pubmed_title":["Microenvironmental ammonia enhances T cell exhaustion in colorectal cancer."],"pmcid":["PMC9841369"],"funding_grant_id":["R01 CA244931","F30 CA257292","P30 CA046592","R01 CA148828","T32 GM007315","R37 CA237421","F99 CA264414","R01 CA248160","T32 GM008322","P01 HL149633","R01 DK095201","F31 CA247457","K08 CA234416","623914","R35 GM130183","R01 CA245546"],"pubmed_authors":["Kim D","Huber AK","Zhang L","Kumar R","Gyorffy B","Singhal R","Sajjakulnukit P","Solanki S","Mehra R","El-Derany MO","Fearon ER","Kerk SA","Banerjee R","Korimerla N","Pasca di Magliano M","Chen B","James JG","Wahl DR","Green M","Das NK","Rebernick RJ","Frankel TL","Bell HN","Gonzalez FJ","Shah YM","Lyssiotis CA"],"additional_accession":[]},"is_claimable":false,"name":"Microenvironmental ammonia enhances T cell exhaustion in colorectal cancer.","description":"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.","dates":{"release":"2023-01-01T00:00:00Z","publication":"2023 Jan","modification":"2025-04-04T03:00:41.274Z","creation":"2025-02-19T01:44:33.438Z"},"accession":"S-EPMC9841369","cross_references":{"pubmed":["36528023"],"doi":["10.1016/j.cmet.2022.11.013"]}}