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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| Hauptverfasser: | , , , , , , , , , , , , , , , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
Jan 2024
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| In: |
Science advances
Year: 2024, Jahrgang: 10, Heft: 3, Pages: 1-16 |
| ISSN: | 2375-2548 |
| DOI: | 10.1126/sciadv.adi2012 |
| Online-Zugang: | 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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| Verfasserangaben: | 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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| 245 | 1 | 0 | |a Tumor cell-intrinsic PD-1 promotes Merkel cell carcinoma growth by activating downstream mTOR-mitochondrial ROS signaling |c 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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| 520 | |a 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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