Enzyme-mediated depletion of methylthioadenosine restores T cell function in MTAP-deficient tumors and reverses immunotherapy resistance

Donjeta Gjuka; Elio Adib; Kendra Garrison; Jianfeng Chen; Yuxue Zhang; Wenjiao Li; Daniel Boutz; Candice Lamb; Yuri Tanno; Amin Nassar; Talal El Zarif; Neil Kale; Mehrdad Rakaee; Tarek H Mouhieddine; Sarah Abou Alaiwi; Alexander Gusev; Thomas Rogers; Jianjun Gao; George Georgiou; David J Kwiatkowski; Everett Stone

doi:10.1016/j.ccell.2023.09.005

Enzyme-mediated depletion of methylthioadenosine restores T cell function in MTAP-deficient tumors and reverses immunotherapy resistance

Cancer Cell. 2023 Oct 9;41(10):1774-1787.e9. doi: 10.1016/j.ccell.2023.09.005. Epub 2023 Sep 28.

Authors

Donjeta Gjuka¹, Elio Adib², Kendra Garrison¹, Jianfeng Chen³, Yuxue Zhang³, Wenjiao Li³, Daniel Boutz⁴, Candice Lamb⁵, Yuri Tanno¹, Amin Nassar⁶, Talal El Zarif⁷, Neil Kale⁸, Mehrdad Rakaee⁹, Tarek H Mouhieddine¹⁰, Sarah Abou Alaiwi², Alexander Gusev¹¹, Thomas Rogers¹², Jianjun Gao³, George Georgiou¹³, David J Kwiatkowski¹⁴, Everett Stone¹⁵

Affiliations

¹ Department of Chemical Engineering, University of Texas, Austin, TX, USA.
² Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA; Lank Genitourinary Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
³ Department of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁴ Department of Molecular Biosciences, University of Texas, Austin, TX, USA.
⁵ Department of Chemical Engineering, University of Texas, Austin, TX, USA; Department of Molecular Biosciences, University of Texas, Austin, TX, USA.
⁶ Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.
⁷ Lank Genitourinary Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
⁸ Worcester Polytechnic Institute, Worcester, MA, USA.
⁹ Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
¹⁰ Division of Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place, New York, NY, USA.
¹¹ Division of Population Sciences, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
¹² Children's Medical Center Research Institute, University of Texas Southwestern, Dallas, TX, USA.
¹³ Department of Chemical Engineering, University of Texas, Austin, TX, USA; Department of Molecular Biosciences, University of Texas, Austin, TX, USA; Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, TX, USA; Department of Oncology, University of Texas Dell Medical School, LiveSTRONG Cancer Institutes, Austin, TX, USA.
¹⁴ Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA. Electronic address: dk@rics.bwh.harvard.edu.
¹⁵ Department of Molecular Biosciences, University of Texas, Austin, TX, USA; Department of Oncology, University of Texas Dell Medical School, LiveSTRONG Cancer Institutes, Austin, TX, USA. Electronic address: stonesci@utexas.edu.

PMID: 37774699
PMCID: PMC10591910 (available on 2024-10-09)
DOI: 10.1016/j.ccell.2023.09.005

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, Non-U.S. Gov't

MeSH terms

Humans
Immunotherapy
Neoplasms* / drug therapy
Neoplasms* / genetics
Protein-Arginine N-Methyltransferases / genetics
Purine-Nucleoside Phosphorylase / genetics
T-Lymphocytes* / metabolism

Substances

5'-methylthioadenosine phosphorylase
Purine-Nucleoside Phosphorylase
PRMT5 protein, human
Protein-Arginine N-Methyltransferases

Abstract

Publication types

MeSH terms

Substances

Grants and funding