The effect of the tumor environment on the anti-tumor immune response

Abstract

Cancer immunotherapy is the process of stimulating the host's immune system to kill cancer cells, and it is being investigated as adjuvant therapy to traditional cancer treatments such as, surgery, radiation therapy and chemotherapy. Two advantages of using immunotherapy are that it employs additional tumor killing strategies, and it often results in modest side effects for patients. However, the success of immunotherapy, based on actual tumor regression, has been modest. The tumor microenvironment has been implicated as one impediment of immune responses elicited to kill tumor cells. Therefore, a better understanding of the molecular events occurring within a progressing tumor will elucidate approaches for improving cancer therapy.

Much of cancer research is focused on studying cell lines maintained in vitro. While there is tremendous value in investigating cultured tumor cell lines, this does not represent the complex interactions occurring in the host during tumor progression. Solid tumors Progress in a microenvironment consisting of in addition to tumor cells, stromal cells, and soluble components and the interactions between these constituents contribute to tumor progression.

In this thesis I present mechanisms associated with tumor establishment and progression in the B16-F10 mouse melanoma model. The first project was a discovery based proteomics study to identify differential protein expression during tumor progression. The whole tumor tissue, including tumor cells and the tumor microenvironment such as non-tumor cells, extracellular matrix, and blood, was analyzed at 4 time stages during tumor progression. Identified proteins from this kinetic proteome analysis elucidated tumorigenic processes during tumor progression.

The second project was a targeted approach by screening proteins that have immunomodulatory properties and that are associated with immune privileged sites. The over expression of macrophage migration inhibitory factor (MIF) in a tumor cell line compared to a syngeneic, nontumor cell line provoked experiments to elucidate the mechanism of MIF's role in tumor establishment and progression. An interfering MIF (iMIF) RNA, and a control interfering RNA (iRNA) were stably introduced into B16-F10 mouse melanoma cells, and inhibition of MIF delayed tumor establishment by one week, implicating MIF as a potential target for solid tumor therapy.