Author's School

Graduate School of Arts & Sciences

Author's Department/Program

Biology and Biomedical Sciences: Immunology

Language

English (en)

Date of Award

Spring 3-6-2013

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Chair and Committee

Robert D Schreiber

Abstract

Accumulated data from animal models and human cancer patients strongly support the concept that immunity cannot only function as an extrinsic tumor suppressor, but also shape tumor immunogenicity. These observations led to the development of the cancer immunoediting hypothesis that stresses the dual host-protective and tumor-sculpting actions of immunity on developing cancers. We previously demonstrated important roles for lymphocytes and type I: IFN-α/β) and type II: IFN-γ) interferons in cancer immunoediting. In the present work, we confirmed the role of IFN-γ in sculpting tumor immunogenicity and provide evidence that antigens expressed by tumors drive the destructive or sculpting actions of immunity on cancers.

Initial studies confirmed the finding that IFN-γ is a critical mediator of cancer immunoediting. Wild type mice treated with antibodies that neutralize IFN-γ developed more sarcomas than control mice. Furthermore, a subset of sarcomas generated in IFN-γ neutralized mice spontaneously reject when transplanted into wild type mice. Finally, these unedited tumors had differential requirements for IFN-γ responsiveness at the level of the host and the tumor to mediate tumor rejection.

Although many immune components that participate in cancer immunoediting are known: e.g. IFN-γ), its underlying mechanisms remain poorly defined. We used massively parallel sequencing to characterize the expressed mutations in a highly immunogenic sarcoma, d42m1, and identified mutant spectrin-β2 as the major rejection antigen. Moreover, we demonstrate that editing of d42m1 tumor cells occurs via a T cell-dependent immunoselection process that promotes outgrowth of variants lacking mutant spectrin-β2. Thus, the strongly immunogenic characteristic of an unedited tumor can be ascribed to expression of a highly antigenic mutant protein.

Subsequent studies established that antigen loss variants of d42m1 and edited sarcomas from wild type mice exhibit residual immunogenicity and respond to checkpoint blockade immunotherapy: anti-CTLA-4). Exome sequencing of these tumors has laid the groundwork for the eventual identification of the antigens targeted for destruction by this form of cancer immunotherapy. Taken together, these studies demonstrate that antigens drive the cancer immunoediting process and point to the future potential that cancer genome sequencing may have on the fields of tumor immunology and cancer immunotherapy.

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Permanent URL: http://dx.doi.org/10.7936/K7C8278N

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