BRAF and MEK Inhibitors Increase PD-1-Positive Melanoma Cells Leading to a Potential Lymphocyte-Independent Synergism with Anti-PD-1 Antibody

• Published in: Clinical cancer research 2018-07, Vol.24 (14), p.3377-3385
• Main Authors: Sanlorenzo, Martina, Vujic, Igor, Floris, Arianna, Novelli, Mauro, Gammaitoni, Loretta, Giraudo, Lidia, Macagno, Marco, Leuci, Valeria, Rotolo, Ramona, Donini, Chiara, Basiricò, Marco, Quaglino, Pietro, Fierro, Maria Teresa, Giordano, Silvia, Sibilia, Maria, Carnevale-Schianca, Fabrizio, Aglietta, Massimo, Sangiolo, Dario
• Format: Article
• Language: English
• Subjects: 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
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-17-1914

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. .