A protein called Meteorin-like (METRNL) in the tumor microenvironment saps energy from T cells, thereby severely limiting their ability to fight cancer, according to new research directed by investigators at the Johns Hopkins University School of Medicine and the Johns Hopkins Kimmel Cancer Center and its Bloomberg~Kimmel Institute for Cancer Immunotherapy.
Finding ways to block the effects of METRNL signaling on tumor-infiltrating T cells may allow these immune cells to regain the energy necessary to eliminate tumors.
A report about the work was published Aug. 6 in the journal Immunity.
In a series of laboratory investigations, researchers first studied T cells from the tumor tissue and blood of patients with previously untreated brain tumors (glioblastomas), prostate cancer, bladder cancer and renal cell/kidney cancer, and performed RNA sequencing to try to identify genes responsible for dysfunction in the tumor. METRNL was the gene most highly expressed.
Next, they wanted to find out what makes T cells secrete METRNL in the first place, discovering that the reason was chronic stimulation. Normally, the immune system activates when stimulated to fight an infection and then diminishes when that illness resolves. But in the setting of cancer, T cells are chronically stimulated, which causes them to become dysfunctional. METRNL also was found to be secreted by other immune cells in tumors such as macrophages and dendritic cells, but it acts specifically on T cells.
Additional study determined that METRNL acts directly on the mitochondria, and decouples the electron transport chain. As T cells lose energy and start to fail, they increase their attempts to use glucose (natural sugar) as a backup source of energy. But, because the tumor environment is low in glucose, they continue to flounder and eventually die. This is one of the ways that tumors can continue to grow. Deleting METRNL in models of different cancer types in the researchers’ investigations universally delayed tumor growth.
Finally, researchers observed that METRNL is activated through a family of transcription factors (proteins that control the rate of transcription of genetic information from DNA to RNA) called E2F, that it is dependent on signaling by a receptor called PPAR delta, and that modulating these factors downstream can block the effects of METRNL.
