35 The role of toll-like receptor (TLR) agonists in combinational immunotherapy for head and neck cancer. Issue 5 (May 2015)

• Record Type: Journal Article
• Authors: Lei, Y.; Li, J.; Srivastava, R.M.; Stephenson, R.; Brandau, S.; Lang, S.; Ferris, R.L.
• Is Part Of: Oral oncology. Volume 51:Issue 5(2015:May)
• Page Start: e38
• Publication Date: 2015-05
• Subjects: Mouth -- Cancer -- Periodicals; Mouth -- Tumors -- Periodicals; Mouth Diseases -- Periodicals; Mouth Neoplasms -- Periodicals; Bouche -- Cancer -- Périodiques; Bouche -- Tumeurs -- Périodiques; Tumeurs -- Périodiques; Electronic journals; 616.9943105
• DOI: 10.1016/j.oraloncology.2015.02.036
• Languages: English
• ISSNs: 1368-8375

Abstract

Abstract : Background: Because of their stimulating effect on manifold components of the innate immune system, TLR-agonists are in the focus of the search for potent drugs in combinational anticancer therapy. They induce the maturation and cross-priming of Dendritic Cells (DC), and have been shown to enhance Natural Killer (NK) cell dependent lysis of tumor cells in combination with monoclonal antibodies (mAb) such as anti-epidermal growth factor receptor (EGFR) cetuximab. One of the reasons that may have limited the full potential of TLR-agonists so far is their sequential induction of suppressive factors as part of the immune system's balancing component. Methods: Peripheral blood mononuclear cells (PBMC), NK, DC and monocytes were isolated and stimulated with different TLR agonists: poly I:C (TLR-3), LPS (TLR-4), VTX-2337 (TLR-8) and CpG (TLR-9). Analysis was performed using flow cytometry, cytokine ELISA, qPCR, T cell stimulation assays with VTX in the presence or absence of anti PD-1 Ab. Furthermore, Tumor-infiltrating Lymphocytes (TIL) of the pre- and post-treatment patient samples of trial patients that undergo a neoadjuvant combinational therapy with the TLR-8 agonist VTX-2337 and anti-EGFR mAb cetuximab were analyzed. Results: TLR-agonists and combinational drugs show an additive effect. TLR8-stimulation enhanced monocyte maturation markers CD80, CD83, and CD86 alone and in co-culture with cetuximab-treated HNC cells. A skewing to the M1 phenotype of monocytes was evidenced by significantly increased secretion of Th1 cytokines TNF α ( p < 0.0001), IFN γ ( p < 0.0001), and IL-12p40 ( p < 0.005). Immature myeloid-derived suppressor cells (MDSC) that were treated with VTX-2337 showed upregulation of maturation markers. Furthermore, the treatment of monocytes with TLR-agonists such as VTX-2337 induced a strong upregulation of the inhibitory marker PD-L1. Discussion: Our work focuses on the maturational effect of TLR agonists on monocytes, their skewing to an M1 phenotype and on the induction of suppressive pathways through surface molecules such as PD-L1. TLR-agonists contain a strong potential in combinational therapies, including drugs that inhibit the sequential induction of checkpoint receptors (e.g. PD-1 blockade, nivolumab) or show additive immune-enhancing effects (e.g. cetuximab).