@article{10b78855f83e400cb18ffb4284102c39,
title = "Enzyme-mediated depletion of methylthioadenosine restores T cell function in MTAP-deficient tumors and reverses immunotherapy resistance",
abstract = "Chromosomal region 9p21 containing tumor suppressors CDKN2A/B and methylthioadenosine phosphorylase (MTAP) is one of the most frequent genetic deletions in cancer. 9p21 loss is correlated with reduced tumor-infiltrating lymphocytes (TILs) and resistance to immune checkpoint inhibitor (ICI) therapy. Previously thought to be caused by CDKN2A/B loss, we now show that it is loss of MTAP that leads to poor outcomes on ICI therapy and reduced TIL density. MTAP loss causes accumulation of methylthioadenosine (MTA) both intracellularly and extracellularly and profoundly impairs T cell function via the inhibition of protein arginine methyltransferase 5 (PRMT5) and by adenosine receptor agonism. Administration of MTA-depleting enzymes reverses this immunosuppressive effect, increasing TILs and drastically impairing tumor growth and importantly, synergizes well with ICI therapy. As several studies have shown ICI resistance in 9p21/MTAP null/low patients, we propose that MTA degrading therapeutics may have substantial therapeutic benefit in these patients by enhancing ICI effectiveness.",
keywords = "Humans, T-Lymphocytes/metabolism, Neoplasms/drug therapy, Purine-Nucleoside Phosphorylase/genetics, Immunotherapy, Protein-Arginine N-Methyltransferases/genetics",
author = "Donjeta Gjuka and Elio Adib and Kendra Garrison and Jianfeng Chen and Yuxue Zhang and Wenjiao Li and Daniel Boutz and Candice Lamb and Yuri Tanno and Amin Nassar and {El Zarif}, Talal and Neil Kale and Mehrdad Rakaee and Mouhieddine, {Tarek H.} and Alaiwi, {Sarah Abou} and Alexander Gusev and Thomas Rogers and Jianjun Gao and George Georgiou and Kwiatkowski, {David J.} and Everett Stone",
note = "Funding Information: This work was supported by funding from R01CA240700 (E.S.) and in part by the Cancer Center Support Grant to MDACC (grant P30CA016672 to J.G.) from the National Cancer Institute, by MD Anderson's Prometheus informatics system and by the Department of Genitourinary Medical Oncology's Eckstein and Alexander Laboratories. J.G. is also supported by the Doris Duke Clinical Scientist Development Award (#2018097), the MD Anderson Physician Scientist Award, Khalifa Physician Scientist Award, Andrew Sabin Family Foundation Fellows Award, MD Anderson Faculty Scholar Award, the David H. Koch Center for Applied Research of Genitourinary Cancers, Wendy and Leslie Irvin Barnhart Fund, Joan and Herb Kelleher Charitable Foundation, KCA Advanced Discovery Award, the Williams TNT Fund, the V Foundation Translational Award, the DOD KCRP Translational Research Partnership Award, NIH/NCI R01 CA254988-01A1, and NIH/NCI R01 CA269489-01A1. Conceptualization, E.S.; Methodology, E.A. D.J.K. and D.B.; Investigation, D.G. E.A. K.G. J.C. Y.Z. W.L. D.B. C.L. Y.T. A.N. T.E.Z. N.K. M.R. T.H.M. S.A.A. A.G. and T.R.; Writing—Original Draft, D.G. E.A. G.G. D.J.K. and E.S.; Writing—Review & Editing, E.A. G.G. D.J.K. and E.S.; Visualization, D.G. E.A. and E.S.; Supervision, E.S. and D.J.K.; Resources, E.S. G.G. J.G. and D.J.K.; Funding Acquisition, E.S. and J.G. Drs. Stone and Gjuka are inventors of intellectual property related to this work. Dr. Georgiou serves as scientific advisory board member for Asher Bio and Amgen. Dr. Gao is an advisory committee member for CRISPR Therapeutics, Jounce Therapeutics, Polaris and Seagen, and a consultant for AstraZeneca, Aveo Pharmaceuticals, Infinity Pharmaceuticals, Janssen, Pfizer, and Symphogen. D. Gjuka and E. Stone are inventors of intellectual property related to this work owned by The University of Texas at Austin. Funding Information: This work was supported by funding from R01 CA240700 (E.S.) and in part by the Cancer Center Support Grant to MDACC (grant P30 CA016672 to J.G.) from the National Cancer Institute , by MD Anderson{\textquoteright}s Prometheus informatics system and by the Department of Genitourinary Medical Oncology's Eckstein and Alexander Laboratories . J.G. is also supported by the Doris Duke Clinical Scientist Development Award (#2018097 ), the MD Anderson Physician Scientist Award, Khalifa Physician Scientist Award, Andrew Sabin Family Foundation Fellows Award, MD Anderson Faculty Scholar Award, the David H. Koch Center for Applied Research of Genitourinary Cancers, Wendy and Leslie Irvin Barnhart Fund, Joan and Herb Kelleher Charitable Foundation , KCA Advanced Discovery Award, the Williams TNT Fund , the V Foundation Translational Award, the DOD KCRP Translational Research Partnership Award, NIH /NCI R01 CA254988-01A1 , and NIH /NCI R01 CA269489-01A1 . Publisher Copyright: {\textcopyright} 2023 Elsevier Inc.",
year = "2023",
month = oct,
day = "9",
doi = "10.1016/j.ccell.2023.09.005",
language = "English (US)",
volume = "41",
pages = "1774--1787.e9",
journal = "Cancer Cell",
issn = "1535-6108",
publisher = "Cell Press",
number = "10",
}