Tumor cell-intrinsic PD-1 promotes Merkel cell carcinoma growth by activating downstream mTOR-mitochondrial ROS signaling

Medientyp: E-Artikel

Titel: Tumor cell-intrinsic PD-1 promotes Merkel cell carcinoma growth by activating downstream mTOR-mitochondrial ROS signaling

Beteiligte: Martins, Christina [Verfasser:in]; Rasbach, Erik [Verfasser:in]; Heppt, Markus V. [Verfasser:in]; Singh, Praveen [Verfasser:in]; Kulcsar, Zsofi [Verfasser:in]; Holzgruber, Julia [Verfasser:in]; Chakraborty, Asmi [Verfasser:in]; Mucciarone, Kyla [Verfasser:in]; Kleffel, Sonja [Verfasser:in]; Brandenburg, Anne [Verfasser:in]; Hoetzenecker, Wolfram [Verfasser:in]; Rahbari, Nuh Nabi [Verfasser:in]; DeCaprio, James A. [Verfasser:in]; Thakuria, Manisha [Verfasser:in]; Murphy, George F. [Verfasser:in]; Ramsey, Matthew R. [Verfasser:in]; Posch, Christian [Verfasser:in]; Barthel, Steven R. [Verfasser:in]; Schatton, Tobias [Verfasser:in]

Erschienen: Jan 2024

Sprache: Englisch

DOI: 10.1126/sciadv.adi2012

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Anmerkungen: Veröffentlicht: 19. Januar 2024

Beschreibung: Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer. Inhibitors targeting the programmed cell death 1 (PD-1) immune checkpoint have improved MCC patient outcomes by boosting antitumor T cell immunity. Here, we identify PD-1 as a growth-promoting receptor intrinsic to MCC cells. In human MCC lines and clinical tumors, RT-PCR-based sequencing, immunoblotting, flow cytometry, and immunofluorescence analyses demonstrated PD-1 gene and protein expression by MCC cells. MCC-PD-1 ligation enhanced, and its inhibition or silencing suppressed, in vitro proliferation and in vivo tumor xenograft growth. Consistently, MCC-PD-1 binding to PD-L1 or PD-L2 induced, while antibody-mediated PD-1 blockade inhibited, protumorigenic mTOR signaling, mitochondrial (mt) respiration, and ROS generation. Last, pharmacologic inhibition of mTOR or mtROS reversed MCC-PD-1:PD-L1-dependent proliferation and synergized with PD-1 checkpoint blockade in suppressing tumorigenesis. Our results identify an MCC-PD-1-mTOR-mtROS axis as a tumor growth-accelerating mechanism, the blockade of which might contribute to clinical response in patients with MCC.

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