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Characterization of Systemic Immune Escape and the Anti-tumor Effects of a Recombinant Vaccinia Virus Expressing HER2/neu in a Mouse Model of HER2/neu-overexpressing Breast Cancer

by
Christiaan R. de Vries
B.A., Rutgers University - 2004



Thesis Advisor: Edmund C. Lattime, Ph.D.
Graduate Program in Microbiology & Molecular Genetics

Cancer Institute of New Jersey - Board Room
195 Little Albany Street
New Brunswick

Tuesday, April 23, 2013
3:00 p.m.


Abstract

The goal of cancer immunotherapy is to develop an immune response capable of overcoming immune escape mechanisms that induce systemic anergy to tumor associated antigens (TAA). We found that orthotopic growth of NBT1, a syngeneic mouse mammary carcinoma that overexpressed Human Epidermal growth factor Receptor-2 (HER2/neu), was associated with increased Gr-1+CD11b+ myeloid derived suppressor cells (MDSCs) both systemically and in the tumor microenvironment of female FVB/N mice. This MDSC population had inhibitory effects on the HER2/neu-specific Th1 immune response. VVneu and VVGMCSF are recombinant vaccinia viruses developed in our laboratory which encode HER2/neu and granulocyte colony stimulating factor (GM-CSF), respectively. In na´ve FVB/N mice, vaccination subcutaneously or into the mammary fatpad with combined VVneu and VVGMCSF resulted in a similar increase in the HER2/neu-specific cytotoxic T lymphocyte (CTL) response. In contrast, in tumor-bearing mice, when VVneu and VVGMCSF were injected with Keyhole Limpet Hemocyanin (KLH), directly into the tumor or subcutaneously in the contralateral side, only vaccination into the tumor microenvironment resulted in a significant increase in CTL activity and regression of NBT1. Moreover, MDSC levels decreased in mice that received local vaccination, while remaining stable in mice treated with subcutaneous vaccine. Having demonstrated that a systemic CTL response could mediate NBT1 regression, we next examined whether using a monoclonal antibody (1D11) to induce systemic inhibition of Transforming Growth Factor-β (TGF-β), a cytokine which interferes with CTL responses, would enhance the CTL response against NBT1. Transcriptome sequencing (RNA-Seq) and immunohistochemistry revealed increased infiltration of T cells in tumors from 1D11 treated mice. Monotherapy with 1D11 did not yield an increased anti-tumor CTL response. However, combination therapy with 1D11 and intratumoral VVneu + VVGMCSF + KLH resulted in an increased HER2/neu-specific CTL response compared to either therapy alone. Notably, this synergistic CTL response was only seen when the vaccine was administered directly into the tumor microenvironment, and not with subcutaneous VVneu + VVGMCSF + KLH. These studies demonstrate a dual role for the tumor microenvironment in both promoting systemic anergy to HER2/neu and providing an effective site for immunization with recombinant poxvirus vaccines encoding TAA in order to overcome MDSC-associated anergy.


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