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Tumor cell-intrinsic PD-1 promotes Merkel cell carcinoma growth by activating downstream mTOR-mitochondrial ROS signaling.
Martins, Christina; Rasbach, Erik; Heppt, Markus V; Singh, Praveen; Kulcsar, Zsofi; Holzgruber, Julia; Chakraborty, Asmi; Mucciarone, Kyla; Kleffel, Sonja; Brandenburg, Anne; Hoetzenecker, Wolfram; Rahbari, Nuh N; DeCaprio, James A; Thakuria, Manisha; Murphy, George F; Ramsey, Matthew R; Posch, Christian; Barthel, Steven R; Schatton, Tobias.
Afiliación
  • Martins C; Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • Rasbach E; Program of Glyco-Immunology and Oncology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • Heppt MV; Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • Singh P; Program of Glyco-Immunology and Oncology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • Kulcsar Z; Department of Surgery, University Hospital Mannheim, Heidelberg University, 68167 Mannheim, Germany.
  • Holzgruber J; Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • Chakraborty A; Department of Dermatology, University Hospital Erlangen, Friedrich-Alexander-University (FAU), 91054 Erlangen, Germany.
  • Mucciarone K; Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • Kleffel S; Program of Glyco-Immunology and Oncology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • Brandenburg A; Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • Hoetzenecker W; Program of Glyco-Immunology and Oncology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • Rahbari NN; Department of Dermatology, University Hospital Bonn, 53127 Bonn, Germany.
  • DeCaprio JA; Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • Thakuria M; Program of Glyco-Immunology and Oncology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • Murphy GF; Department of Dermatology and Venerology, Johannes Kepler University, 4020 Linz, Austria.
  • Ramsey MR; Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • Posch C; Program of Glyco-Immunology and Oncology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • Barthel SR; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • Schatton T; Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Sci Adv ; 10(3): eadi2012, 2024 Jan 19.
Article en En | MEDLINE | ID: mdl-38241371
ABSTRACT
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-1PD-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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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Cutáneas / Carcinoma de Células de Merkel Límite: Humans Idioma: En Revista: Sci Adv Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Cutáneas / Carcinoma de Células de Merkel Límite: Humans Idioma: En Revista: Sci Adv Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos