Abstract
Cancer is a group of diseases characterised by uncontrolled proliferation and metastasis of malignant cells throughout the body which if not treated leads to death. Melanoma is a form of skin cancer that accounts for less than 5% of skin cancers, but is responsible for approximately 80% of skin cancer related deaths. Melanoma is characterised by an aggressive clinical behaviour, is associated with metastasis, and responds poorly to chemo-and radiotherapy. Immunotherapeutic strategies, such as cancer vaccines, are designed to inhibit melanoma cell proliferation by inducing cell death, and offer a promising less toxic treatment option.
Effective immunotherapeutic cancer vaccines require the induction of robust anti-tumour immune responses resulting in the destruction and elimination of the developing tumour. This requires elements of both the innate and adaptive immune system. However, many factors hinder the induction of anti-tumour immune responses. Tumour cells release pro-inflammatory factors which result in the blocking of normal immune cell differentiation and the accumulation of pro-tumour populations, myeloid-derived suppressor cells (MDSCs) are once such population. MDSCs exert potent immunosuppressive, pro-tumour effects. The role of MDSCs in cancer progression is becoming clearer and the targeting of their pro-tumour actions a promising therapy for cancer. Key factors responsible for MDSC proliferation are prostaglandins and leukotrienes, produced through the enzymatic actions of cyclooxygenase and lipoxygenase, respectively. Disrupting the function of either of these enzymes may result in a reduction in MDSC activities.
The hypothesis tested here is that treatment of MDSCs with licofelone, a dual cyclooxygenase and lipoxygenase inhibitor, would reduce the production of suppressive factors and the suppressive action of MDSCs.
In order to test these hypothesises, MDSCs were generated from hematopoietic stem cells, treated with licofelone and the hallmarks of MDSC suppression were evaluated in vitro. The effect of blocking MDSC activity in vivo was evaluated by treating tumour-bearing mice with licofelone and a therapeutic peptide-based cancer vaccine formulated into cationic liposomes and administered via various routes and schedules.
Data from these experiments showed that licofelone suppressed the production of interleukins -6 and -10 by MDSC, and increased the production of reactive oxygen species in a time and concentration dependent manner. Preliminary experiments suggest licofelone reverses MDSC-mediated CD8+ T cell suppression in vitro. Vaccine formulations containing licofelone, the melanoma peptide antigen tyrosinase-related protein 2 and the adjuvant α-galactosylceramide, prolonged the survival of tumour-bearing mice when these three components were delivered in combination. The administration of the individual components offered no benefits and intravenous delivery conferred best therapeutic effects.
In conclusion, licofelone inhibited the production of factors associated with MDSC activation and accumulation, as well as suppression. The observations herein also suggest a cyclooxygenase and lipoxygenase independent mechanism of action may exist as regards MDSC functions. Finally, the use of licofelone, tyrosinase-related protein 2, and α-galactosylceramide prepared in cationic liposomes offers a promising vaccine candidate for the treatment of melanoma.