Author ORCID Identifier

0000-0003-2396-0197

Date of Graduation

12-2017

Document Type

Dissertation (PhD)

Program Affiliation

Immunology

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Michael Curran

Committee Member

Chantale Bernatchez

Committee Member

Joya Chandra

Committee Member

Roza Nurieva

Committee Member

Kimberly Schluns

Abstract

T cells comprise a substantial arm of the immune system and are exquisitely adapted to combat pathogens and tumors. The inflammatory environment largely dictates the nature of T cell response. A hallmark of T cell-mediated immunity is formation of immunological memory; the ability to respond more potently to re-encounter with pathogens. The immune system is also capable of recognizing tumors as foreign, much like viral or bacterial pathogens. Tumors have evolved, though, to generate an immunosuppressive environment to avoid destruction. The field of immunotherapy seeks to overcome immune suppression, in part by targeting T cell co-receptors on the cell surface with either agonist or antagonist antibodies. Targeting the T cell co-stimulatory receptor 4-1BB with agonist antibodies engenders strong antitumor responses in multiple murine tumor models, in part by expanding the proliferative capacity, survival, and cytotoxicity of T cells within the tumor microenvironment. We have previously shown that systemic administration of α4-1BB antibodies induces a novel T cell program typified by expression of the T-box transcription factor Eomesodermin (Eomes) and the co-inhibitory receptor Killer Cell Lectin-like Receptor G1 (KLRG1) which we collectively term ThEO.

Herein, we demonstrate that the ThEO phenotype constitutes a stable T cell polarity capable of recalling to subsequent antigen challenge. Despite expression of terminal differentiation markers, ThEO cells phenotypically resemble discrete memory T cell subsets. We also find that the activation of the Signal Transducer and Activator of Transcription (STAT) pathways, in particular STAT1 and STAT3, is critical to ThEO polarization.

ThEO cells possess clinical relevance. Anti-4-1BB antibodies synergize with HPV peptide vaccination to eradicate HPV+ murine tumors, due to a honed tumor-specific ThEO response. Further, ThEO phenotype cells infiltrate the livers of α4-1BB treated mice, which may play a role in 4-1BB mediated hepatotoxicity. Finally, we show that melanoma patients enrolled in α4-1BB clinical trials upregulate key markers associated with the ThEO phenotype; hence formation of ThEO cells within patient blood may act as a biomarker for therapeutic outcome.

This body of work demonstrates that the ThEO phenotype constitutes a unique T cell polarity that may prove beneficial in cancer treatment.

Keywords

4-1BB, tumor immunology, immunotherapy, immunological memory, hepatitis, HPV, signaling

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