Programmed cell death 1 (PD-1) inhibitors have been approved for treating various types of cancer, but PD-1 functions can vary between different cell and cancer types, either promoting or suppressing disease progression.
Merkel cell carcinoma (MCC) responds well to immune checkpoint inhibitor therapy, but it unknown if MCC cells express PD-1 themselves. In addition, researchers haven’t known how cancer cell-intrinsic PD-1 contributes to tumor growth in MCC.
Now, investigators from Brigham and Women’s Hospital have identified a novel mechanism through which PD-1 promotes MCC progression. Through a series of experiments, the researchers demonstrated PD-1 expression on MCC cells in preclinical models and patient tumor samples. They found that MCC-PD-1 receptor binding to its ligands accelerated tumor growth by activating the mammalian target of rapamycin (mTOR) pathway and generating mitochondrial reactive oxygen species (mtROS) to promote MCC growth.
Then, the authors showed that inhibiting mTOR signaling and neutralizing mtROS suppressed MCC-PD-1-mediated tumor proliferation in mice. These findings might help in the development of new treatments to halt MCC progression even in patients lacking T-cell immunity, the study authors conclude.
“For the first time, our work identifies PD-1 as an MCC-intrinsic receptor that promotes tumor growth via downstream mTOR signaling and mitochondrial reactive oxygen species production,” says corresponding author Tobias Schatton, PharmD, PhD, of the Department of Dermatology, in a news release. “Targeting this tumor-intrinsic PD-1 signaling network could help optimize immune checkpoint therapy regimens and improve MCC patient outcomes.”
The study appears in Science Advances.
