Researchers may have uncovered novel mechanisms contributing to the progression of Merkel cell carcinoma, according to a recent study published by Martins et al in Science Advances. PD-1 immune checkpoint inhibitors have already shown success in improving patient outcomes in this space through antitumor T-cell activity. In the study, researchers used human Merkel cell carcinoma lines and clinical tumors to conduct reverse transcription polymerase chain reaction (RT-PCR)–based sequencing, immunoblotting, flow cytometry, and immunofluorescence analyses. The researchers found PDCD1 gene and PD-1 protein expression by Merkel cell carcinoma cells. Additionally, in vitro proliferation and in vivo tumor xenograft growth was enhanced following Merkel cell carcinoma–PD-1 ligation and suppressed following its inhibition. Protumorigenic mTOR protein signaling, mitochondrial respiration, and mitochondrial ROS generation were induced following Merkel cell carcinoma–PD-1 binding and blocked following antibody-mediated PD-1 inhibition. Lastly, Merkel cell carcinoma–PD-1/PD-L1–dependent proliferation was reversed following pharmacologic inhibition of mTOR or mictochondrial ROS and tumorigenesis was suppressed in combination with PD-1 inhibition. The researchers underscored that the Merkel cell carcinoma–PD-1–mTOR–mitochondrial ROS axis may promote accelerated tumor growth and its inhibition may be an effective treatment option in patients with the disease.
February 07, 2024