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

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...

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Main Authors: Martins, Christina (Author) , Rasbach, Erik (Author) , Heppt, Markus V. (Author) , Singh, Praveen (Author) , Kulcsar, Zsofi (Author) , Holzgruber, Julia (Author) , Chakraborty, Asmi (Author) , Mucciarone, Kyla (Author) , Kleffel, Sonja (Author) , Brandenburg, Anne (Author) , Hoetzenecker, Wolfram (Author) , Rahbari, Nuh Nabi (Author) , DeCaprio, James A. (Author) , Thakuria, Manisha (Author) , Murphy, George F. (Author) , Ramsey, Matthew R. (Author) , Posch, Christian (Author) , Barthel, Steven R. (Author) , Schatton, Tobias (Author)
Format: Article (Journal)
Language:English
Published: Jan 2024
In: Science advances
Year: 2024, Volume: 10, Issue: 3, Pages: 1-16
ISSN:2375-2548
DOI:10.1126/sciadv.adi2012
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1126/sciadv.adi2012
Verlag, kostenfrei, Volltext: https://www.science.org/doi/10.1126/sciadv.adi2012
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Author Notes:Christina Martins, Erik Rasbach, Markus V. Heppt, Praveen Singh, Zsofi Kulcsar, Julia Holzgruber, Asmi Chakraborty, Kyla Mucciarone, Sonja Kleffel, Anne Brandenburg, Wolfram Hoetzenecker, Nuh N. Rahbari, James A. DeCaprio, Manisha Thakuria, George F. Murphy, Matthew R. Ramsey, Christian Posch, Steven R. Barthel, Tobias Schatton
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Summary: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.
Item Description:Veröffentlicht: 19. Januar 2024
Gesehen am 01.08.2024
Physical Description:Online Resource
ISSN:2375-2548
DOI:10.1126/sciadv.adi2012

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