On Tuesday 29 September 2020, Ulla Kring Hansen will defend her PhD thesis "Characterisationof mutatedand viraltumor epitopesand theirimplicationin checkpoint inhibitor therapy".
Time: 9:00
Place: Zoom, sign up here: https://dtudk.zoom.us/meeting/register/u5cvf-yqrz8oGNYkDIv2rD7p-dlemp9AtNE0
Principal supervisor: Professor Sine Reker Hadrup
Examiners:
Associate Professor Katharina Lahl, DTU Health Tech
Professor Tanja D. de Gruijl, VU university medical centre
PD Dr. rer.natJan Dörrie, Universitätsklinikum Erlangen
Chairperson at defence:TBA
Abstract:
The gained insight into the immune system’s role in tumor control and elimination has created a paradigm shift in cancer treatment options with immunotherapy as a major contributor. Immune checkpoint inhibitors are the most advanced immunotherapy available cable steering T cells towards the tumor through an unspecific stimulation. Despite its success, a large fraction of patients does not benefit from such therapy. Instead, precision targeted immunotherapies could be attractive strategies since these aim to steer the T cells towards a specific target on the tumor cells. The research presented in this thesis aims to identify and characterize such T cell targets and investigate the role of the specific T cells in the immune response following checkpoint inhibition therapy. The first part of the thesis focuses on mutated peptides, which give rise to neoepitopes. In research paper I, we reported the first identification T cell recognition of neoepitopes in renal cell carcinoma with frameshift-derived neoepitopes being an important immune target due to low similarity to wild type peptide. In research paper II, we reported findings based on a meta-analysis of four different cancer cohorts, that T cell recognition of human leukocyte antigen-C bound neoepitopes plays a substantial or even dominating role in tumor recognition compared to the two other human leukocyte antigen subtypes, -A and –B. In research paper III, we presented preliminary results monitoring the induction of neoepitope-specific T cells during checkpoint inhibition therapy in a cohort across various cancer types, and found that non-progressive disease patients tended to have higher amounts of mutations, neopeptide load, and neoepitope-specific T cells. Future evaluation of additional patients will potentially elucidate the therapeutic mechanism. The second part of this thesis focuses on the virus-associated cancer Merkel Cell Carcinoma driven by the expression of viral oncoproteins, called T antigens. In research paper IV, we describe 11 novel epitopes originating from the T antigens, which are solely patient-specific, and present evidence that T cells can recognizing several of these epitope on the tumor surface. Lastly, we presented results from a preliminary investigation of Merkel Cell Carcinoma patients treated with checkpoint inhibition therapy, where we solely detected T cells recognizing T antigens in patients responding to therapy. These early indications need to be validated with additional patients and potentially result in the first evidence of T cell recognition of T antigens as the underlying mechanism for response to therapy. All together, these research studies presented in this thesis provide novel insight into defining an ideal T cell target that can facilitate the development of precision targeted immunotherapies to improve the current immunotherapies available.