Melanoma Cell-Intrinsic PD-1 Receptor Functions Promote Tumor Growth
| Autor: | Nayoung Lee, Vikram R. Juneja, Steven R. Barthel, Markus H. Frank, Keith T. Flaherty, George F. Murphy, Arlene H. Sharpe, Antonio Cozzio, Tobias Schatton, Christine G. Lian, Martin C. Mihm, Reinhard Dummer, Christian Posch, Emmanuella Guenova, Rahel Thomi, Sonja Kleffel, Qian Zhan, Christopher P. Elco, Thomas S. Kupper, Christoph Schlapbach, Wolfram Hoetzenecker, Hansgeorg Mueller |
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| Přispěvatelé: | University of Zurich, Schatton, Tobias |
| Rok vydání: | 2015 |
| Předmět: |
Programmed Cell Death 1 Receptor
programmed cell death-1 p-S6 medicine.disease_cause B7-H1 Antigen Mice 0302 clinical medicine S6 ribosomal protein antibody PD-1 Melanoma Cells Cultured 0303 health sciences 10177 Dermatology Clinic Acquired immune system 3. Good health Gene Knockdown Techniques 030220 oncology & carcinogenesis Heterografts Signal transduction Signal Transduction Tumor Graft PD-L1 610 Medicine & health Antineoplastic Agents Biology Article General Biochemistry Genetics and Molecular Biology 03 medical and health sciences 1300 General Biochemistry Genetics and Molecular Biology Cell Line Tumor Blocking antibody medicine Animals Humans immune checkpoint neoplasms 030304 developmental biology therapy Biochemistry Genetics and Molecular Biology(all) blockade medicine.disease Mice Inbred C57BL Immunology mTOR signaling Cancer research biology.protein Carcinogenesis Neoplasm Transplantation |
| Zdroj: | Cell. 162:1242-1256 |
| ISSN: | 0092-8674 |
| DOI: | 10.1016/j.cell.2015.08.052 |
| Popis: | Therapeutic antibodies targeting programmed cell death-1 (PD-1) activate tumor-specific immunity and have shown remarkable efficacy in the treatment of melanoma. Yet, little is known about tumor cell-intrinsic PD-1 pathway effects. Here we show that murine and human melanomas contain PD-1-expressing cancer subpopulations and demonstrate that melanoma cell-intrinsic PD-1 promotes tumorigenesis, even in mice lacking adaptive immunity. PD-1 inhibition on melanoma cells by RNA interference, blocking antibodies, or mutagenesis of melanoma-PD-1 signaling motifs suppresses tumor growth in immunocompetent, immunocompromised and PD-1-deficient tumor graft recipient mice. Conversely, melanoma-specific PD-1 overexpression enhances tumorigenicity, as does engagement of melanoma-PD-1 by its ligand, PD-L1, whereas melanoma-PD-L1 inhibition or knockout of host-PD-L1 attenuate growth of PD-1-positive melanomas. Mechanistically, the melanoma-PD-1 receptor modulates downstream effectors of mTOR signaling. Our results identify melanoma cell-intrinsic functions of the PD-1:PD-L1 axis in tumor growth and suggest that blocking melanoma-PD-1 might contribute to the striking clinical efficacy of anti-PD-1 therapy. |
| Databáze: | OpenAIRE |
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