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.
METRNL has been described in the medical literature before — initially as playing a role in helping keep cold or exercising animals (and people) warm by poking holes in the mitochondria (energy factory) of fat cells so they produce heat. However, it had not previously been known to be active in cancer or in T cells, says lead study author Christopher Jackson, M.D., an assistant professor of neurosurgery at Johns Hopkins.
When T cells try to eliminate a tumor, the state of chronic stimulation/stress causes them to secrete METRNL, Jackson explains. Once METRNL is secreted, it interacts with the mitochondria and pokes holes in the electron transport chain, a cluster of proteins participating in a process to create energy. When T cells can no longer keep up with their energy requirements, they stop trying to kill cancer cells, which enables cancer cells to multiply and spread.
"Others have shown that metabolic dysfunction limits T cells' ability to fight cancer, but we are among the first to describe a discrete signaling pathway that causes that to happen," Jackson says. "Most of the previous work has looked at how the lack of specific nutrients in tumors limits a T cell's ability to function. The problem is this is difficult to modify because it's hard to get the right nutrients into a tumor and direct them to T cells. We potentially can do much better by targeting a signaling pathway because we can block it or turn it on or off, but until now, nobody had identified such a pathway that restores the metabolic health of T cells in tumors."
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.
The next steps are to determine how this can help patients, Jackson says. He and his colleagues are actively working on different means to target the METRNL-E2F-PPAR delta pathway or to combine targeted treatment with other immunotherapies.
"We think that one of the reasons that some current immunotherapies fail is they require more energy from immune cells that already are functioning at decreased capacity," he says. "Blocking the pathway may allow these immunotherapies that maybe have not been effective in the past to be more effective because there will be enough fuel for the T cells to meet that increased demand."
Study co-authors were Ayush Pant, Aanchal Jain, Eli Yazigi, Liang Zhao, Thomas Nirschl, Christina Kochel, Denis Routkevitch, Kisha Patel, Stephany Tzeng, Sarah Neshat, Barbara Smith, Jordan Green, Chetan Bettegowda, Henry Brem and Drew Pardoll of Johns Hopkins. Additional study co-authors who were at Johns Hopkins at the time the research was conducted were Wikum Dinalankara and Luigi Marchionni of Weill Cornell Medicine in New York, Charles Drake of Janssen Research and Michael Lim of Stanford School of Medicine in Palo Alto, California. Other investigators from Stanford and Asan Medical Center in Seoul, South Korea, contributed to the project.
RNA sequencing was supported by grants through the Bristol Myers Squibb International Immuno-Oncology Network and Janssen Pharmaceuticals. Dinalankara and Marchionni were supported by the National Institutes of Health-National Cancer Institute award R01CA200859.
Jackson is a consultant for Egret Therapeutics with equity interests in the company. He is an inventor on a patent filed by The Johns Hopkins University for using immune checkpoint agonists to treat cerebrovascular disorders. He receives research support from Biohaven, InCephalo and Grifols. His work is funded by philanthropy and the Goldhirsh-Yellin Foundation. The Johns Hopkins University has filed a provisional patent on METRNL blockade for cancer treatment, on which Jackson, Pant, Brem and others are inventors.
Additionally, Bettegowda is a consultant for Depuy-Synthes and Bionaut Labs. Brem is a consultant for Perosphere, AsclepiX Therapeutics, StemGen, Accelerating Combination Therapies, Catalio Nexus Fund II LLC, LikeMinds Inc., Acuity Bio Corp., InSightec, Galen Robotics and Nurami Medical. These relationships are managed by The Johns Hopkins University in accordance with its conflict-of-interest policies.
