Characterisation of mutated and viral tumor epitopes and their implication in checkpoint inhibitor therapy

Research output: Book/ReportPh.D. thesisResearch

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 (ICI) are the most advanced immunotherapy available cable of reinvigorate the functional capacity of T cells and thereby steering them 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 ICI therapy. The first part of the thesis focuses on mutated peptides, which give rise to neoepitopes. In paper I, we reported the first identification of neoepitope-specific T cells in renal cell carcinoma. We investigated the role of multiple tumor sources (tumor fragment and tumor cell line) for mutational analysis to predict neoepitopes and found that even though a substantial overlap was observed, each tumor source contributed with unique neoepitopes. Mutational analysis could thus benefit from including both tumor fragment and tumor cell line when possible. Tumors from renal cell carcinoma patients present with the highest number of frameshift mutations, which alter the genomic sequence substantially compare to single nucleotide variants (SNVs). We evaluated the immunogenicity towards both mutation types and found that neoepitopes from frameshift mutations were enriched in fraction compared to SNV, and showed significantly lower similarity to wild type sequence. Such low self-similarity makes these neoepitopes particularly interesting in precision targeted immunotherapy, due to the low risk of auto-reactivity. In paper II, we performed a metaanalysis across four cancer cohorts to evaluate the contribution of all three human leukocyte antigen (HLA) haplotypes to present neoepitopes recognized by T cells. HLA-Cs have long been neglected in the studies of tumor immunogenicity. Despite the fact that we confirm the lower expression levels of these HLA alleles, we reported that HLA-C restricted neoepitopes play a substantial or even dominating role in tumor cell recognition, arguing that such HLA-C alleles should be included in future epitope characterization studies and potential therapies. In paper III, we present preliminary results monitoring the induction of neoepitope-specific T cells during ICI therapy in a pan-caner cohort. We evaluated the mutational burden and neopeptide load explored from tumor biopsies taken before and after therapy initiation. We found that non-progressive disease patients tended to have increased mutational burden and neopeptide load and with a significantly higher overlap between the two time points for both parameters. We then evaluated the T cell induction following therapy and observed a tendency for increased numbers of neoepitope-specific T cells in non-progressive disease patients in both tumor and peripheral blood samples with an almost exclusive recognition of frameshift-derive neoepitopes in these patients. We also observed an overall survival benefit associated with the presence of these neoepitope-reactive T cells. This is an ongoing study and an additional evaluation of seven more patients is required to validate these indications for elucidating the potential therapeutic mechanisms.
The second part of this thesis focuses on the virus-associated cancer Merkel Cell Carcinoma (MCC) driven by the expression of oncoviral antigens, T antigens (T-Ag). In paper IV, we expanded the knowledge of epitopes embedded in the T-Ags, through the report of 11 novel T-Ag-derived epitopes, which are solely patient-specific. We also evaluated the functional capacity of such T cells and presented evidences of anti-tumor response mediated by T-Ag reactive T cells. We thereby increased the repertoire of epitopes to use in potentially targeted immunotherapy approaches. ICI therapy is highly effective in MCC, and we aimed to explore if T-Ag-specific T cell induction explains the high anti-tumor responses after therapy. A preliminary investigation of ICI treated MCC patients is presented in the additional result section, and we here observed an induction of TAg-specific T cells solely in patients responding to therapy. These early indications need to be validated with additional patients and potentially result in the first evidence of T-Ag-mediated tumor recognition as the underlying mechanism response to ICI therapy in MCC.
All together, these research studies presented in this thesis provide novel insight into defining an ideal epitope target that can elicit a strong T cell response leading to tumor elimination. The two chosen tumor antigen groups, neoantigens and oncoviral antigens, are both highly tumor-specific, which makes them attractive for targeted approaches due to the reduced risk of off-target toxicity. Potentially enabling the use of such epitopes in precision targeted strategies is highly relevant for improving the current immunotherapy strategies.
Original languageEnglish
PublisherDTU Health Technology
Number of pages161
Publication statusPublished - 2020

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