Rosenthal, Rachel Suzanne;
(2018)
Immune editing and surveillance in cancer evolution.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Cancer is an evolutionary disease, reliant on genetic diversity and sculpted by selective forces from the immune microenvironment. Here, I use genomics data to decipher the tumor’s evolutionary trajectory and corresponding shifts in the immune contexture to elucidate the events governing tumor immunogenicity and the immune evasive mechanisms evolved by the tumor. To better understand the mutational processes contributing to intratumor heterogeneity in individual tumors, a method to quantify the activity of mutational processes in a single tumor sample was developed and applied to temporally dissected mutations. The clinical relevance of intratumor heterogeneity was examined in the context of immune recognition and modulation. Increased clonal neoantigen burden and minimal neoantigen intratumor heterogeneity were found to associate with improved patient outcome, both in the treatment-naïve and immunotherapy-treated setting. The identification of T-cells recognizing clonal neoantigens further supported the clinical importance of targeting neoantigens present in every cancer cell. Mechanisms of immune evasion were considered through the development of a method to identify loss-of-heterozygosity at the HLA locus, overcoming the challenges posed by the polymorphic nature of the locus. HLA loss-of-heterozygosity was found to be a frequent subclonal event in NSCLC, under strong selective pressure and associated with increased subclonal neoantigen burden. Finally, the immune microenvironment was examined through multi-region RNAseq, permitting the quantification of immune infiltration and allowing for the identification of heterogeneously immune infiltrated tumors. Supporting the interplay between genetic events and the immune contexture, a relationship between the genomic features of the tumor and immune infiltration was observed, with HLA loss-of-heterozygosity specifically identified as occurring within a highly active immune microenvironment. This thesis shows how an improved understanding of the relationship between the tumor and the immune system can illuminate features dictating immune recognition and evasion and how that knowledge may inform the development and implementation of successful immunotherapy.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Immune editing and surveillance in cancer evolution |
| Event: | UCL (University College London) |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10047362 |
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