Loss of the "housekeeping" gene methylthioadenosine phosphorylase, or MTAP, is a common event in cancer. Patients with melanoma or bladder cancer whose tumor cells lack a functioning version of the gene tend not to respond to immune checkpoint inhibitors, although the reasons haven't been clear. In this study, researchers at Dana-Farber and the University of Texas MD Anderson Cancer Center found that the deletion of MTAP creates a buildup of the protein MTA within tumor cells. The cells secrete most of the MTA into the extracellular space, where it impedes the growth and activity of cancer-fighting T cells of the immune system. The researchers hypothesized that MTA-degrading enzymes could reduce MTA levels in the tumor microenvironment, restoring T cell function and improving the effectiveness of immune checkpoint inhibitors. Tests of this approach in tumor models showed this to be the case: the number of active T cells rose, and tumor growth slumped.
The deletion of MTAP is primarily responsible for the decline in T cell function and lack of response to immune checkpoint inhibitors in patients whose tumor cells lack working copies of this gene. Drugs that deplete MTA have the potential to enhance the effectiveness of checkpoint inhibitors in these patients.
National Cancer Institute grants R01 CA240700, P30 CA016672, R01 CA254988-01A1, and R01 CA269489-01A1; MD Anderson's Prometheus informatics system and its Department of Genitourinary Medical Oncology's Eckstein and Alexander Laboratories; a Doris Duke Clinical Scientist Development Award; 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 Department of Defense KCRP Translational Research Partnership Award; and NIH/NCI.
Gjuka, D., et al. (2023). Enzyme-mediated depletion of methylthioadenosine restores T cell function in MTAP-deficient tumors and reverses immunotherapy resistance. Cancer Cell. doi.org/10.1016/j.ccell.2023.09.005.