Enzyme-mediated depletion of methylthioadenosine restores T cell function in MTAP-deficient tumors and reverses immunotherapy resistance
Published in Cancer Cell, 2023
Recommended citation: Gjuka, D., Adib, E., Garrison, K., Chen J., Zhang Y., Li W., Boutz D., Lamb C., Tanno Y., Nassar A., Zarif T., Kale N., Rakaee M., Mouhieddine T., Alaiwi A., Gusev A., Rogers T., Gao J., Georgiou G., Kwiatkowski D., Stone E. (2023). "Enzyme-mediated depletion of methylthioadenosine restores T cell function in MTAP-deficient tumors and reverses immunotherapy resistance." Cancer Cell, 41. 1-14. https://doi.org/10.1016/j.ccell.2023.09.005
In this research, I developed a Python/R pipeline to identify deleterious variants in a cohort of 1,842 Dana-Farber Cancer Institute patients and conducted a Cox regression survival analysis of tumors with CDKN2A/MTAP deletions. My work helped to identify loss of MTAP (methythioadenosine phosphorylase), not CDKN2A as was previously thought, leads to poor outcomes in immune checkpoint inhibitor (ICI) therapy. We propose several methylthioadenosine (MTA) degrading therapeutics that consequently may substantially benefit patients by improving ICI effectiveness.