Author ORCID Identifier

0000-0002-0633-1615

Date of Graduation

6-2021

Document Type

Dissertation (PhD)

Program Affiliation

Biostatistics, Bioinformatics and Systems Biology

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

P. Andrew Futreal

Committee Member

Patrick Hwu

Committee Member

Alexander J. Lazar

Committee Member

Nicholas Navin

Committee Member

Han Liang

Committee Member

Hussein Tawbi

Committee Member

Linghua Wang

Abstract

Intratumor heterogeneity (ITH) is a crucial challenge in cancer treatment. The genotypic and phenotypic heterogeneity underlying diverse cancer types leads to subclonal variation, which may result in mixed or failed response to therapy. The heterogeneity at the tumor level, along with the tumor microenvironment (TME), often shapes tumor evolution and ultimately clinical outcome. Given that modern treatment paradigms increasingly expose patients with metastatic disease to multiple treatment modalities through the course of their disease, there exists a need to characterize robust and predictive biomarkers of response to therapy. In order to accurately characterize tumor evolution, we need to account for both intra-tumoral genomic factors as well as how these factors interact with the components of the tumor microenvironment to allow for response and resistance to various forms of therapy.

Through multidimensional profiling of a tumor and its cellular ecosystem we assessed spatial heterogeneity in response to ICB in metastatic melanoma and highlighted the effects of copy number alterations being associated to varied immune phenotypes. We characterized localized regions of immune activation by both T and B cells however, sub-regions with chromosome 7 gain displayed a distinct lack of immunocytic infiltrate but evidence of neutrophil activation that was recapitulated in TCGA samples and was associated with lack of response to ICB across three separate cohorts.

Through a longitudinal sampling strategy paired to a clinical trial, we characterized the impact of heterogeneity on therapy outcomes after combination ICB agents in multiple sarcoma histologies. Amongst the genomic, transcriptomic and immune-based molecular correlates analyzed, elevated intratumoral levels of B cells were most significantly correlated with response at both time-points, as measured by both gene expression and immunostaining. Responsive tumors were also associated with higher diversity and richness of the intratumoral T cell repertoire at baseline.

In order to characterize the effects of the immune-tumor microenvironment, we used multiplex immunofluorescence to quantitatively analyze T-cell subsets and sequenced the T-cell receptors of matched Barrett’s Esophagus (BE) and Esophageal adenocarcinoma (EAC) samples from our patient cohort. Through our work we identified a more infiltrated and diverse immune microenvironment in EAC as compared to BE, however this was primarily characterized by an immunosuppressive T-cell infiltrate, the clonal expansion of which may have been limited with public antigenicity.

In summary, our work frames the spatial and temporal molecular features of heterogeneity characterized across tumors and their surrounding microenvironment, and how their interplay in turn may influence disease progression, tumor evolution and response to therapy.

Keywords

Genomics, Melanoma, Sarcoma, Oncology, Immune Checkpoint Blockade, Predictors of Response, Immunogenomics, Tumor Microenvironment, Intratumor Heterogeneity, Spatial Heterogeneity

Available for download on Thursday, June 15, 2023

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