Author's School

Graduate School of Arts & Sciences

Author's Department/Program

Biology and Biomedical Sciences: Immunology

Language

English (en)

Date of Award

5-24-2010

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Chair and Committee

Robert Schreiber

Abstract

The idea that a functionally intact immune system can protect against cancer development forms the basis of the long-postulated and once controversial concept of cancer immunosurveillance. A substantial body of evidence, however, now exists defining a role for immunity in extrinsic tumor suppression - work that broadened our understanding of the tumor-immune interface and led to the cancer immunoediting hypothesis. The interferons, both type I: IFNα/β) and type II IFN: IFNγ), are critical mediators of cancer immunoediting, yet their respective roles in promoting anti-tumor immune responses remain unclear. Herein, we have examined the actions of IFNα/β and IFNγ during tumor rejection, providing evidence for distinct functions on the host as well as the tumor. We have established that host hematopoietic cells represent important targets of IFNα/β's actions, however these cytokines can have potent stimulatory effects on both innate and adaptive immune cells. Using bone marrow chimeras, we demonstrated that IFNα/β sensitivity within innate immune cells, but not T or B lymphocytes, was essential for the priming of tumor-specific T cells and the generation of protective immunity. Whereas NK cells were not required for IFNα/β-dependent tumor rejection, CD8α+ dendritic cells were critical, and the direct actions of type I IFN on CD8α+ DCs enhanced antigen cross-presentation. When we instead examined the requirements for IFNγ during tumor rejection, we observed an important function for both hematopoietic and nonhematopoietic host cell sensitivity, as well as a more prolonged duration of action. Selective reconstitution and RNAi knockdown of IFNGR1 also corroborated the importance of tumor cell responsiveness to IFNγ, but not IFNα/β. As exogenous type I IFN has shown clinical efficacy in cancer therapy, we performed similar studies using a model of IFNβ immunotherapy. We observed that local production of IFNβ could induce either reversible tumor equilibrium: at higher doses) or elimination: at lower doses). The effects of high-dose IFNβ were independent of adaptive immunity and required hematopoietic and nonhematopoietic IFNα/β responsiveness; in contrast, tumor elimination with low-dose IFNβ required adaptive immunity and responsiveness only in hematopoietic cells. Collectively, these studies add to our understanding of the protective functions of the interferons during anti-tumor immunity.

Comments

Permanent URL: http://dx.doi.org/10.7936/K7D798DG

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