Evaluating Molecular Characteristics of Diverse Clinical Outcomes in Clear Cell Renal Cell Carcinoma
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Embargo End Date
2028-06-09
ICR Authors
Authors
Tippu, Z
Document Type
Thesis or Dissertation
Date
2025-06-09
Date Accepted
Abstract
Clear cell renal cell carcinoma (ccRCC) is characterised by a diversity of clinical phenotypes, yet clinically implementable biomarkers to
guide decision making are lacking. Effors to date have been limited by a reliance on single biomarkers and a failure to account for
intratumoral heterogeneity, a pervasive feature of ccRCC. Additionally, profiling efforts are often temporally disconneccted, with sampling
pre-dating systemic treatment, often by deveral years. Across three cohorts, leveraging single and multi-regional sampling approaches,
I have sought to characterise tumour molecular and immune microenvironmental features associated with differential clinico-pathological
features and survival outcomes.
Genomics biomarkers were explored across two-large scale cohorts, integrating single and multi-regional approaches with nuanced
clinical annotation. In a subset of patients undergoing deferred cytoreductive nephrectomies, dynamic changes in the tumour immune
microenvironement were identifed, which underpind durable responses to combination Ipilimumab-Nivolumab. To address the limitations
of biomarker discovery, the MANIFEST profiling platform was developed, with the aim of generating composite bimarker signatures
capable of better reconciling differential responses to immunotherapy.
Integrated genomic biomarkers have the potential to reconcile the diversity of clinical phenotypes in ccRCC, particularly when combined
with clinico-pathological features to optimise relapse prediction and when accounting for the context in which individual gene mutations
occur. Durable responses to immune checkpoint inhibitors are critically underpinned by dynamic changes in the tumour immune
microenvironement. The development of multimodal biomarkers that account for intratumoral heterogeneity, integrate dynamic features,
and incorporate both mutational and microenvironmental features is required to better predict theyrapy outcome and reconcile the
clinical diversity of ccRCC
Citation
2025
DOI
Source Title
Publisher
Institute of Cancer Research (University Of London)
ISSN
eISSN
Collections
Research Team
Melanoma & Kidney Cancer