Studies on local APC and HPV-specific T cells as prelude to the immunotherapy of human tumors

In this thesis, several aspects and cellular players involved in the immune response to (HPV-induced) tumors were investigated. In chapter 2 a detailed analysis of HPV-specific immunity in a large group of patients with HPV-induced cervical cancer (CxCa) in relation to HLA-types and prognostic factors was performed. In 30% of the tested patients, circulating HPV specific T cells were found, most often in patients with deeply infiltrating tumors. In this group, patients with HPV specific proliferative immunity displayed better disease free survival. It was shown earlier by Piersma et al [69] that only in 30% of TIL populations, HPV specific T cells were found. In chapter 3 an in depth analysis of the breadth and type of HPV specific T-cell populations in tumor infiltrating T cell (TIL) cultures or LN cells from HPV 16 or 18 positive CxCa patients was performed. We found that if patients displayed a HPV-specific T cell response, this was surprisingly broad. Despite recognition, a number of cells did not produce type 1 cytokines and therefore we tested what TLR-agonist was able to support cytokine induction by these T cells. In chapter 4 we asked the question whether HPV-specific T cells play a role in HPV-induced HNSCC. We hypothesize that HPV-induced tumors are more immunogenic and stimulate strong T-cell reactivity to the viral oncoproteins in contrast to HPV-negative tumors. We set up a pilot study to investigate whether HPV is present in HNSCC in the Dutch patient population and at which anatomical site. Accordingly, blood and tumor infiltrating T cells were analyzed for the presence of functional HPV specific T cells. The lack of T cell responses in CxCa patients and the __poised__ function of tumor-antigen specific T cells could be a lack of proper priming by DC. Therefore we investigated in chapter 5A the effects of CxCa produced soluble factors on the differentiation of antigen presenting cells (APC). Several tumor cell lines hampered DC differentiation or even skewed monocyte differentiation into tolerogenic tumor promoting M2 macrophages. We identified the factors responsible for this and investigated the outcome of the interaction of HPV specific T-cell clones with these macrophages. Since patients with advanced or recurrent disease are treated with platinum based chemotherapy we investigated the immune-modulating effect of this therapy on tumor cells, tumor-modulated APC and subsequent interaction with T cells. This ongoing work is summarized in