Clinical cancer research, 2018-07, Vol.24 (14), p.3377-3385
2018
Details
- Autor(en) / Beteiligte
- Titel
- BRAF and MEK Inhibitors Increase PD-1-Positive Melanoma Cells Leading to a Potential Lymphocyte-Independent Synergism with Anti-PD-1 Antibody
- Ist Teil von
- Clinical cancer research, 2018-07, Vol.24 (14), p.3377-3385
- Ort / Verlag
- United States: American Association for Cancer Research Inc
- Erscheinungsjahr
- 2018
- Link zum Volltext
- Quelle
- Electronic Journals Library
- Beschreibungen/Notizen
- BRAF and MEK inhibitors (BRAF/MEKi) favor melanoma-infiltrating lymphocytes, providing the rationale for current combinatorial trials with anti-PD-1 antibody. A portion of melanoma cells may express PD-1, and anti-PD-1 antibody could have a direct antitumor effect. Here, we explore whether BRAF/MEKi modulate rates of PD-1 melanoma cells, supporting an additional-lymphocyte-independent-basis for their therapeutic combination with anti-PD-1 antibody. With data mining and flow cytometry, we assessed PD-1, PD-L1/2 expression on melanoma cell lines (CCLE, = 61; validation cell lines, = 7) and melanoma tumors (TCGA, = 214). We explored how BRAF/MEKi affect rates of PD-1 , PD-L1/2 melanoma cells, and characterized the proliferative and putative stemness features of PD-1 melanoma cells. We tested the functional lymphocyte-independent effect of anti-PD-1 antibody alone and in combination with BRAF/MEKi and in an immunodeficient murine model. PD-1 is consistently expressed on a small subset of melanoma cells, but PD-1 cells increase to relevant rates during BRAF/MEKi treatment [7.3% (5.6-14.2) vs. 1.5% (0.7-3.2), = 0.0156; = 7], together with PD-L2 melanoma cells [8.5% (0.0-63.0) vs. 1.5% (0.2-43.3), = 0.0312; = 7]. PD-1 cells proliferate less than PD-1 cells (avg. 65% less; = 7 days) and are preferentially endowed with stemness features. , the direct anti-melanoma activity of PD-1 blockage as monotherapy was negligible, but its association with BRAF/MEKi significantly delayed the development of drug resistance and tumor relapse. BRAF/MEKi increase the rates of PD-1 melanoma cells that may sustain tumor relapse, providing a lymphocyte-independent rationale to explore combinatory strategies with anti-PD-1 antibody. .
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1078-0432eISSN: 1557-3265DOI: 10.1158/1078-0432.CCR-17-1914Titel-ID: cdi_proquest_miscellaneous_2025313916
- Format
- –
- Schlagworte
- Animal models, Animals, Anticancer properties, Antineoplastic Agents, Immunological - pharmacology, Antineoplastic Agents, Immunological - therapeutic use, Antitumor activity, Biotechnology, Cancer, Cell Cycle - drug effects, Cell Cycle - genetics, Cell Line, Tumor, Combinatorial analysis, Data mining, Data processing, Disease Models, Animal, Drug resistance, Drug Synergism, Experimental design, Flow cytometry, Gene Expression, Genes, Reporter, Humans, Immunodeficiency, Inhibitors, Lymphocytes, Lymphocytes - immunology, Lymphocytes - metabolism, MEK inhibitors, Melanoma, Melanoma - drug therapy, Melanoma - genetics, Melanoma - immunology, Melanoma - metabolism, Mice, Mice, Transgenic, Mitogen-Activated Protein Kinase Kinases - antagonists & inhibitors, PD-1 protein, PD-L1 protein, Programmed Cell Death 1 Receptor - antagonists & inhibitors, Programmed Cell Death 1 Receptor - genetics, Programmed Cell Death 1 Receptor - metabolism, Protein Kinase Inhibitors - pharmacology, Protein Kinase Inhibitors - therapeutic use, Proto-Oncogene Proteins B-raf - antagonists & inhibitors, Synergism, Tumors, Xenograft Model Antitumor Assays