The Roots of Neurofibromas in Neurofibromatosis 1 — A Question of Multipotency, Differentiation and Hiding

Neurofibromatosis type 1 (NF1) is an autosomal dominant cancer predisposition syndrome that affects about 1 in 3500 individuals worldwide. NF1 is caused by mutations in the NF1 gene that encodes the tumor suppressor protein neurofibromin, an inactivator of the Ras oncogene. The hallmarks of NF1 include pigmentary lesions of the skin, Lisch nodules of the iris and cutaneous neurofibromas. Cutaneous neurofibromas are benign tumors composed of all the cell types of normal peripheral nerve. The traditional view of neurofibroma development has been that cutaneous neurofibromas arise from the disruption of the small nerve tributaries of the skin and subsequent proliferation of the resident cells. The second hit mutation in the NF1 gene has been considered as a prerequisite for neurofibroma development. The second hit is detectable in a subpopulation of primary Schwann cells cultured from neurofibromas. This thesis challenges the traditional concept of neurofibroma development. The results show that cutaneous neurofibromas are intimately associated with hair follicular structures and contain multipotent precursor cells (NFPs), suggesting that neurofibromas may arise from the multipotent cells which reside in hair follicles. Furthermore, this study presents that neurofibroma-derived Schwann cells that harbor bi-allelic inactivation in the NF1 gene express HLA class II genes and may act as nonprofessional antigen presenting cells. The CD4- and FoxP3-positive cells detected in cutaneous neurofibromas suggest that these cells may represent regulatory T cells (Tregs) which interact with HLA II –positive cells and aid the tumor cells in hiding from the immune system and are thus mediators of immune tolerance. This thesis also investigated neurofibroma development in the oral cavity and the use of different biomarkers to characterize cellular differentiation in neurofibromas. The results revealed that oral neurofibromas are not rare, but they usually appear as solitary lesions contrary to multiple cutaneous neurofibromas and present high heterogeneity within and between tumors. The use of class III beta-tubulin as a marker for neuronal differentiation led to an unexpected finding showing that multiple cell types express class III beta-tubulin during mitosis. The increased understanding of the multipotency of tumor cells, cellular differentiation and ability to hide from immune system will aid in the development of future treatments. Specifically, targeting Tregs in NF1 patients could provide a novel therapeutic approach to interfere with the development of neurofibromas.

Compulsory licensing of standard-essential patents and injunctive relief as abuse of dominant position in violation of Article 102 TFEU

When a dominant undertaking holding a standard-essential patent uses its exclusive right to the IP to seek injunctions against those wishing to produce either de jure or de facto standard compliant products, it creates a conflict between the exclusive right to the use of the IP on the one hand and the possible abuse of dominance due to the exclusionary conduct on the other. The aim of the thesis is to focus on the issues concerning abuse of dominance in violation of Article 102 TFEU when the holder of the standard-essential patent seeks an injunction against a would-be licensee. The thesis is mainly based on the most recent ECJ case law in Huawei and the Commission’s recent decisions in Samsung and Motorola. The case law in Europe prior to those decisions was mainly focused on the German case law from Orange Book Standard which provided IP holders great leverage due to the almost automatic granting of injunctions against infringers. The ECJ in Huawei set out the requirements for when a de jure standard-essential patent holder would not be violating Article 102 TFEU when seeking an injunction, requiring that negotiations in good faith must take place prior to the seeking of the injunction and that all offers must comply with FRAND terms, thus limiting the scope of case law derived from Orange Book Standard in Germany. The ECJ chose not to follow all of the reasoning the Commission had laid out in Samsung and Motorola which provided a more licensee-friendly approach on the matter, but rather chose a compromise between the IP holder friendly German case law and the Commission’s decisions. However, the ECJ did not disclose how FRAND terms themselves should be interpreted, but rather left it for the national courts to decide. Furthermore, the thesis strongly argues that Huawei did not change the fact that only vertically integrated IP holders who have made a FRAND declaration are subject to the terms laid out in Huawei, thus leaving non-practicing entities such as patent trolls and entities that have not made a FRAND declaration outside its scope. The resulting conclusion from the thesis is that while the ECJ in Huawei presented new exceptional circumstances for when an IP holder could be abusing its dominant position when it seeks an injunction, it still left many more questions answered, such as the meaning of FRAND and whether deception in giving a FRAND declaration is prohibited under Article 102 TFEU or not.