In the clinic, several forms of immunotherapy are combined with the standard treatments, including chemotherapy. Translational studies trying to understand the different outcomes in patients have... Show moreIn the clinic, several forms of immunotherapy are combined with the standard treatments, including chemotherapy. Translational studies trying to understand the different outcomes in patients have led to new questions and hypotheses. The studies described in this thesis are to answer some of these questions. We revealed the immunostimulatory effect of the chemotherapy agent; cisplatin. Next, we studied the mechanism of relapse following immunotherapy with HPV16 SLP vaccination in mice. We demonstrated that unsuccessful immunotherapy results in immune editing and secondary resistance. To overcome this, the combination therapies are required. Moreover, we showed the importance of IL-6 producing by tumors in dampening anti-tumor response. To induce a long-term sustained effector T cell response, we examined the potency of mouse cytomegalovirus as a viral vector-based vaccine. We demonstrated that the demarcated thresholds of vaccine-specific T cells correlate to tumor protection. Recognizing the fact that at each phase of the antitumor immune response a different type of help might have to be provided to obtain maximal therapeutic efficacy, the correct timing of various types of chemotherapeutic agents or immune modulators when used in combination is discussed. Finally, we discussed the general aspects and relevance of the studies mentioned in this thesis. Show less
The immune system plays an important role in the balance between viral clearance and viral persistence in HPV related (pre)malignant lesions. In this thesis, we analyzed HPV clade A9-specific T... Show moreThe immune system plays an important role in the balance between viral clearance and viral persistence in HPV related (pre)malignant lesions. In this thesis, we analyzed HPV clade A9-specific T-cell responses in relation to virological and clinical outcome to gain further insight into HPV-specific cellular immunity in relation to the natural course of disease. In depth analysis of cellular immune responses against the E6 antigen of HPV16 and the closely related members of clade A9 (HPV31, 33, 35, 52 and 58) showed us that HPV-specific cross-reactive CD4+ T cells are rare and unlikely to mediate cross protection (chapter 2). The clinical course of cervical HPV infection and HPV-specific immune responses in prospective studies are described in chapter 4 and 5. In those chapters, a strong correlation is observed between a persistent HPV infection or progressive disease and the lack or failure of a type-specific immune response (>90% of the cases). No correlation is detected between HPV type-specific cellular immune responses and virological clearance of the infection and HPV type-specific immunity may be associated with clearance of a cervical HPV induced lesion (chapter 4 and 5). Interestingly, a statistically significant trend could be detected between the presence of a type-specific immunity (HPV16E2) and regression of a low-grade lesion (chapter 5). A similar, but - due to small number of patients __ not statistically significant trend was observed in chapter 4. Together, this suggests that the local innate immune system might play a role in the clearance of transient infections, whereas the cellular immune response can play a role in regression of histologically proven HPV induced lesions. Detection of HPV16 type-specific cellular immune responses in vivo, by the use of a DTH skin test, confirmed that cellular immune responses in healthy subjects consist of both HPV-specific CD4+ Th1/Th2 and CD8+ T cells (chapter 3). Show less
