The first part of this thesis provides insight in prognostic markers in VSCC to refine clinicopathological risk assessment. One of the most frequently described risk factors for recurrent disease... Show moreThe first part of this thesis provides insight in prognostic markers in VSCC to refine clinicopathological risk assessment. One of the most frequently described risk factors for recurrent disease is the minimal peripheral surgical margin. In order to improve the quality of future studies and clinical recommendations, we provided a practical guideline on how to uniformly measure this margin in chapter 2. We also determined the clinical relevance of the molecular classification of VSCC based on immunohistochemical staining for p16 and p53. In chapter 3 we described the immunohistochemical characterization of these molecular subtypes to aid their detection in routine clinical practice. We utilized this approach to show the difference in clinical outcome between the three distinct molecular subtypes of VSCC in chapter 4.The second part of this thesis contains studies on the tumor microenvironment as a first step towards immunotherapy for VSCC. An overview of the literature concerning immunity in VSCC at the start of our studies is provided in chapter 5. Subsequently, we interrogated the TME of different VSCC subtypes in chapter 6, and showed that high infiltration of CD4+ T cells is important for clinical outcome, irrespective of the molecular subtype of VSCC. In chapter 7 we performed an in-depth analysis on the TME based on RNA profiles and showed that highly T cell infiltrated VSCC are potentially eligible candidates for immunotherapy. In chapter 8 we exploited the expression of CD39 by CD4+ and CD8+ T cells as a marker to identify tumor specific T cells. Finally, in chapter 9 the general aspects and relevance of the studies mentioned in this thesis are combined, discussed, and placed in a broader perspective with suggestions for future research. Show less
Vulvar intraepithelial neoplasia is a chronic premalignant disease caused by a persistent human papillomavirus infection for which conventional surgical therapies are only partially successful with... Show moreVulvar intraepithelial neoplasia is a chronic premalignant disease caused by a persistent human papillomavirus infection for which conventional surgical therapies are only partially successful with high recurrence rates and psychosexual problems. Immunotherapy is a new form of therapy that stimulates the body__s own immune system to resolve infections and cancers. uVIN is the first HPV-induced disease successfully treated by immunotherapy, stressing the capacity of the immune system to deal with disease. Despite these considerable successes of immunotherapy, there is a need to identify parameters of the immune system which allow to select patients most likely to respond to treatment as well as to understand why others do not respond. The studies in this thesis resulted in the identification of a number of immuneparameters that positively or negatively predict the course of disease. These may be of great use as new prognostic biomarkers to identify patients most likely to respond to current successful immune therapeuties or identify patients at risk to the recurrent or progressive course of the disease. Moreover the knowledge of the immune profile may help to understand the non-responsiveness to immunotherapy of some patients. This can be used to optimize these therapies and to foster individualised (immune) therapies. Show less
Cervical cancer is caused by the human papillomavirus (HPV). The immune system plays an important role in the protection against HPV and failure of the immune system can lead to the development of... Show moreCervical cancer is caused by the human papillomavirus (HPV). The immune system plays an important role in the protection against HPV and failure of the immune system can lead to the development of cervical cancer. Immunotherapy aims at the restoration of an effective anti-tumour immunity. This thesis has led to new insights into the role of the immune system in HPV induced disease and forms a vital contribution to our understanding of tumor inducted immunesuppresion in patients with (pre-) cancerous lesions of the cervix. Furthermore it describes two clinical trails in which patients with pre-cancerous lesions of the cervix are vaccinated with an HPV16 E6/E7 synthetic overlapping long-peptide vaccine (HPV16-SLP). Multiple mechanisms restrain the host__s immune system to rise to the challenge of combating the tumour and favourable immune profiles need boosting in order to keep the balance in favour of tumour eradication. Future therapy should combine various synergistic approaches, and old and new therapies should be used side by side in order to enhance vaccination efficacy and counteract tumour suppression. Show less
