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Title

Imaging of Cancer Immunoediting

Date of Award

Spring 5-15-2014

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Immunology)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

Previous work from our lab and others demonstrates the host-protective functions of individual immune components during the elimination phase of cancer immunoediting. Despite the known components involved during elimination, relatively little is known about (1) the evolving nature of lymphocytes and myeloid cells during the course of the elimination phase, from initial recognition to tumor destruction; (2) the effector mechanisms that lead to tumor cell death; and (3) the in vivo behavior of different immune cell populations and their interactions with tumor cells. In the present work, using two-photon microscopy (2PM), we examined the role of dendritic cells (DCs) during tumor elimination, especially their in vivo behavior and interactions with tumor cells.

We transplanted GFP-labeled, highly immunogenic MCA sarcoma cells into CD11c-reporter mice and followed the course of the response. We observed rapidly migrating CD11c-YFP cells interacting with GFP tumor cells during the early phase. Additionally, some cells that resembled CD11c-YFP cells also contained high amounts of GFP. These events were not seen in mice treated with a monoclonal antibody (MAR1-5A3), which blocks the type I interferon (IFN) receptor.

Previous work done in collaboration with Dr. Kenneth Murphy's group showed that CD8α+ DCs and CD103+ DCs are required for induction of host protective anti-tumor responses. Moreover, data from our lab also indicate that type I IFN sensitivity on CD8α+ DCs and CD103+ DCs is critical for the host-protective elimination phase of cancer immunoediting. CD103+ DCs are known to be the major migratory population in the skin, and studies have shown that type I IFNs can enhance the motility of dendritic cells. Therefore, we hypothesized that the rapidly migrating cells are CD103+DCs, and their motility is dependent on type I IFNs. Using the Itgax-Cre+EGFP+Ifnar1f/f mice, we examined how the lack of type I IFN sensitivity, specifically in the CD8α+ DCs, the CD103+ DCs, and a subset of CD4+DCs, affects their in vivo activity during the course of tumor rejection. Using 2-PM and flow cytometry, we found that type I IFN sensitivity on the CD103+ DC population is important for their infiltration to the tumor and their subsequent migration to the lymph node. Further in vitro assays using bone marrow-derived dendritic cells showed that the migration stimulatory effects of type I IFNs can be attributed to the induction of CCR7 expression. Migration of CD103+ DCs from tumor to lymph node was impaired in CCR7 knockout mice, confirming the importance of this receptor in the process.

In vitro studies using bone marrow derived CD103+DCs showed that the initial recognition of tumor cells by CD103+ DCs and their subsequent activation are dependent on type I IFNs. Cross presentation by these cells was also hampered due to the absence of type I IFNs sensitivity. Taken together, these studies indicate the importance of type I IFN sensitivity on CD103+ DCs for their migration, maturation, and antigen cross-presentation to initiate an effective antitumor T-cell response.

Language

English (en)

Chair and Committee

Robert D Schreiber

Committee Members

Marco Colonna, Paul Allen, Mark Miller, Kenneth Murphy, Andrey Shaw

Comments

Permanent URL: https://doi.org/10.7936/K74F1NNQ

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