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

Abstract

// Eran Brauner 1, * , Viswanath Gunda 1, * , Pierre Vanden Borre 1 , David Zurakowski 2, 3 , Yon Seon Kim 1, 4 , Kate Virginia Dennett 1 , Salma Amin 1 , Gordon James Freeman 5 , Sareh Parangi 1 1 Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA 2 Departments of Surgery, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA 3 Departments of Anesthesia, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA 4 Department of Surgery, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea 5 Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA * These authors have contributed equally to this work Correspondence to: Sareh Parangi, e-mail: sparangi@partners.org Keywords: anaplastic thyroid cancer, programmed cell death-1, programmed cell death-ligand 1, BRAF inhibitor, MEK inhibitor Received: November 25, 2015     Accepted: February 06, 2016     Published: March 02, 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). BRAF V600E cells showed significantly higher baseline expression of PD-L1 at mRNA and protein levels compared to BRAF WT cells. MEK inhibitor treatment resulted in a decrease of PD-L1 expression across all cell lines. BRAFi treatment decreased PD-L1 expression in BRAF V600E cells, but paradoxically increased its expression in BRAF WT cells. BRAF V600E mutated patients samples had a higher level of PD-L1 mRNA compared to BRAF WT (p=0.015). Immunocompetent mice (B6129SF1/J) implanted with syngeneic 3747 BRAF V600E/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±174.6mm 3 at two weeks. The combination dramatically reduced tumor volume to 147.3±60.8, compared to PLX4720 (439.3±188.4 mm 3 , 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.