Combining BRAF inhibitor and anti PD-L1 antibody dramatically improves tumor regression and anti tumor immunity in an immunocompetent murine model of anaplastic thyroid cancer

• Published in: Oncotarget 2016-03, Vol.7 (13), p.17194-17211
• Main Authors: Brauner, Eran, Gunda, Viswanath, Vanden Borre, Pierre, Zurakowski, David, Kim, Yon Seon, Dennett, Kate Virginia, Amin, Salma, Freeman, Gordon James, Parangi, Sareh
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Animals; Antibodies, Monoclonal - pharmacology; Antineoplastic Combined Chemotherapy Protocols - pharmacology; B7-H1 Antigen - antagonists & inhibitors; Cell Proliferation - drug effects; Female; Humans; Indoles - pharmacology; Male; Mice; Middle Aged; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins B-raf - antagonists & inhibitors; Proto-Oncogene Proteins B-raf - genetics; Research Paper; Sulfonamides - pharmacology; Thyroid Carcinoma, Anaplastic - drug therapy; Thyroid Carcinoma, Anaplastic - immunology; Thyroid Carcinoma, Anaplastic - pathology; Thyroid Neoplasms - drug therapy; Thyroid Neoplasms - immunology; Thyroid Neoplasms - pathology
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.7839

The interaction of programmed cell death-1 and its ligand is widely studied in cancer. Monoclonal antibodies blocking these molecules have had great success but little is known about them in thyroid cancer. We investigated the role of PD-L1 in thyroid cancer with respect to BRAF mutation and MAP kinase pathway activity and the effect of anti PD-L1 antibody therapy on tumor regression and intra-tumoral immune response alone or in combination with BRAF inhibitor (BRAFi). BRAFV600E cells showed significantly higher baseline expression of PD-L1 at mRNA and protein levels compared to BRAFWT cells. MEK inhibitor treatment resulted in a decrease of PD-L1 expression across all cell lines. BRAFi treatment decreased PD-L1 expression in BRAFV600E cells, but paradoxically increased its expression in BRAFWT cells. BRAFV600E mutated patients samples had a higher level of PD-L1 mRNA compared to BRAFWT (p=0.015). Immunocompetent mice (B6129SF1/J) implanted with syngeneic 3747 BRAFV600E/WT P53-/- murine tumor cells were randomized to control, PLX4720, anti PD-L1 antibody and their combination. In this model of aggressive thyroid cancer, control tumor volume reached 782.3±174.6mm3 at two weeks. The combination dramatically reduced tumor volume to 147.3±60.8, compared to PLX4720 (439.3±188.4 mm3, P=0.023) or PD-L1 antibody (716.7±62.1, P