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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.
- Source :
-
Oncotarget [Oncotarget] 2016 Mar 29; Vol. 7 (13), pp. 17194-211. - Publication Year :
- 2016
-
Abstract
- 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<0.001) alone. Immunohistochemistry analysis revealed intense CD8+ CTL infiltration and cytotoxicity and favorable CD8+:Treg ratio compared to each individual treatment. Our results show anti PD-L1 treatment potentiates the effect of BRAFi on tumor regression and intensifies anti tumor immune response in an immunocompetent model of ATC. Clinical trials of this therapeutic combination may be of benefit in patients with ATC.
- Subjects :
- Adult
Aged
Aged, 80 and over
Animals
Antibodies, Monoclonal pharmacology
Cell Proliferation drug effects
Female
Humans
Male
Mice
Middle Aged
Protein Kinase Inhibitors pharmacology
Proto-Oncogene Proteins B-raf genetics
Thyroid Carcinoma, Anaplastic immunology
Thyroid Carcinoma, Anaplastic pathology
Thyroid Neoplasms immunology
Thyroid Neoplasms pathology
Antineoplastic Combined Chemotherapy Protocols pharmacology
B7-H1 Antigen antagonists & inhibitors
Indoles pharmacology
Proto-Oncogene Proteins B-raf antagonists & inhibitors
Sulfonamides pharmacology
Thyroid Carcinoma, Anaplastic drug therapy
Thyroid Neoplasms drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1949-2553
- Volume :
- 7
- Issue :
- 13
- Database :
- MEDLINE
- Journal :
- Oncotarget
- Publication Type :
- Academic Journal
- Accession number :
- 26943572
- Full Text :
- https://doi.org/10.18632/oncotarget.7839