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Dissertation
Big data analytics and cancer biology: lessons in taking science from the processor to the patient
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Spring 2020
DOI: 10.17077/etd.005280
Abstract
The immune system provides a harsh selection pressure for tumors to develop mechanisms to evade destruction. Tumors can function to subvert adaptive immune activation by decreasing expression of major histocompatibility complex I molecules to prevent the activating signal or through directing the T cell differentiation and activity. The latter is a diverse set of methods involving the interaction of cells in the tumor microenvironment and can function by increasing infiltration of immunosuppressive regulatory T cells (Tregs), myeloid-derived suppressor cells, decreasing antigen presentation, the secretion of suppressive cytokines/chemokines, or the overexpression of negative regulators of immune response, so-called immune checkpoints. Therapies which elicit an anti-tumor immune response, either by directly stimulating an immunogenic response or targeting inhibitory pathways, have long been sought after. My studies focus on promoting or directing the immune response by overcoming the tumor-mediated suppression and increasing response to immunotherapies.
A major predictive correlate of immune checkpoint blockades is tumor mutational load. Although possessing high levels of genomic instability, the aggressive basal-like breast cancer does not respond well to immune checkpoint blockade. My work identifies both an increased level and poor prognostic indication of the DNA mismatch repair proteins, MSH2 and MSH6, in basal-like breast cancer. Lynch syndrome is a familial disorder with germline defects in DNA mismatch repair, a hallmark of these tumors is dense immune infiltration. Conversely, we found the increasing level of MSH2 protein in basal-like breast cancer was associated with decreased immune signatures, notably in lymphocyte, NK cell, and myeloid cell signatures. The genetic ablation of Msh2 in basal-like breast cancer models led to significant reduction in tumor growth and an increase in survival time. The addition of the anti-PD-1 immunotherapy led to a further reduction in tumor growth and increase in T-cell infiltration in tumors from Msh2 knockout versus Msh2 wild-type cells. This work indicates altering the DNA repair process may act as an adjuvant for tumor immunotherapy and increase efficacy of immune checkpoint blockade in aggressive breast cancers.
Another critical component of the tumor microenvironment is the suppressive pressure of Tregs. Analysis of single-cell RNA sequencing of immune cells from both renal and hepatocellular tumors found heterogeneity among Tregs, with tumor-infiltrating Tregs containing distinct, overlapping expression patterns between the two cancer types. Further analysis of other datasets identified several genes commonly differentially regulated in tumor-infiltrating Tregs compared to peripheral-blood Tregs, one of which was CD177. We confirmed the presence of CD177 on of tumor-infiltrating Tregs, but not peripheral-blood Tregs, in humans and found increased expression of several suppressive markers and chemokine receptors on CD177+ breast and renal cancer-infiltrating Tregs compared to CD177- Tregs. Initial human and mouse studies found that tumor-infiltrating CD177+ Tregs were more suppressive than CD177- Tregs in ex vivo suppression assays. Furthermore, we found the removal of Cd177 led to decrease tumor growth in both breast and colorectal mouse models. Taken together, this work lays a foundation for better targeting of tumor-infiltrating Tregs by identifying novel markers of suppressive Treg subsets.
Beyond characterization of immune cell infiltrates of solid tumors, my work also examines the heterogeneity within blood malignancies. Cutaneous T cell lymphomas (CTCL), encompassing a spectrum of T-cell lymphoproliferative disorders involving the skin, have collectively increased in incidence over the last 40 years. Sézary syndrome (SS) is an aggressive form of CTCL characterized by significant presence of malignant cells in both the blood and skin. The guarded prognosis for SS reflects a lack of reliably effective therapy, due in part to an incomplete understanding of disease pathogenesis. Using single-cell sequencing of RNA, we confirmed that SS is a clonal disease by virtue of shared T-cell receptor VDJ expression and CDR3 sequence, but we further defined a more complex model featuring distinct transcriptomic states within SS. Furthermore, we developed methodologies to utilize the transcriptomic diversities in SS to predict disease stage. This work offers insight into the heterogeneity of SS, providing better understanding of the transcriptomic diversities within a clonal tumor, which can predict tumor stage and thereby offer guidance of therapy.
Although a diverse set of projects, my studies focus on the axis of immune-tumor interaction and the development of computational methods to identify targets to improve immunotherapies. In finding the poor prognostic indication of DNA mismatch repair constituents in basal-like breast cancer, my work identifies MSH2 and MSH6 as novel tumor promoters in the context of immune evasion. Furthermore, the analysis of transcriptional heterogeneity of tumor-infiltrating Tregs is the first demonstration of unique gene expression patterns of Tregs in tumors, which can be used to predict survival. Similarly, my work shows the heterogeneity of CTCL cells could be a major underlying cause of the development resistance and poor outcomes in the treatment of advanced SS.
Details
- Title: Subtitle
- Big data analytics and cancer biology: lessons in taking science from the processor to the patient
- Creators
- Nicholas Craig Borcherding
- Contributors
- Weizhou Zhang (Advisor)Adam Dupuy (Committee Member)Munir Tana (Committee Member)Ronald Weigel (Committee Member)Frank Zhan (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Pathology
- Date degree season
- Spring 2020
- DOI
- 10.17077/etd.005280
- Publisher
- University of Iowa
- Number of pages
- xiii, 107 pages
- Copyright
- Copyright 2020 Nicholas Craig Borcherding
- Comment
- This thesis has been optimized for improved web viewing. If you require the original version, contact the University Archives at the University of Iowa: https://www.lib.uiowa.edu/sc/contact/
- Language
- English
- Description illustrations
- color illustrations
- Description bibliographic
- Includes bibliographical references (pages 84-107).
- Public Abstract (ETD)
If I may borrow terminology from my time in the Marine Corps infantry, cancer is a war on oneself. For the last 50 years, oncologists have fought this war with broad, non-specific strategies like chemotherapy and radiation that cause collateral damage to the individual patient and lasting repercussions on health. More recently, the dawn of targeted therapies is like introducing snipers to the battlefield, increasing the accuracy of the therapy against tumors and reducing the side effect profiles of cancer treatments. However, targeted therapies generally have a limited effective window of time, as the tumor develop tactics to avoid the therapies, what is termed resistance. In the modern era of cancer combat, an emerging strategy is using the immune system to fight the tumor. My work focuses on how to arm and direct the immune system against a tumor, limiting the collateral damage of chemotherapies and resistance of targeted therapies. In this sense, having the immune system fight cancer functions to produce a force that can evolve with the tactics that the cancer might develop, leading to more profound, long-term responses. The limitation currently in this strategy is identifying patients that may benefit from the immunotherapy and trying to better activate the immune system for patients that would not respond initially.
- Academic Unit
- Pathology
- Record Identifier
- 9983956198002771
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