MECHANISMS THAT REGULATE TUMOR SPECIFIC IMMUNE RESPONSES

Providence Portland Medical Center, Portland OR

Investigators

Linked publications & trials

Abstract

The mechanism of tumor regression following adoptive transfer of tumor-specific T cells is not cell characterized. Our results suggest that multiple mechanisms are involved. A tumor-specific T1 response appears critical to the generation of a therapeutic antitumor response in naive animals. However, results using T cells obtained from tumor-bearing mice and IFN-gamma ko animals demonstrate that IFN-gamma is not required for therapeutic efficacy. This raises at least two possibilities: (1) that the T1 cytokine profile is only associated with therapeutic efficacy or (2) that T1 cytokines other than IFN-gamma can mediate tumor regression. This proposal will address these possibilities by carefully examining the role that the T1/T2 paradigm plays in our model of T cell-mediated tumor regression. Specifically, we will focus on understanding the mechanisms that regulate whether a tumor induces a predominantly T1 or T2 response, what the spectrum of that cytokine response is, and how the tumor-bearing state influences this response. We will examine whether the defect in TBM is the result of a polarized T2 response (immune deviation) or a functional silencing (anergy) of the tumor-specific T1 response (peripheral tolerance). Finally, we will exploit these insights and test whether they can be used to augment antitumor immunity. This proposal will test our basic hypothesis at multiple points and allow us to develop general principles that could be translated into novel vaccine strategies for patients with cancer. The specific aims of our proposal are as follows: 1) To determine the mechanisms that regulate the development of T1 and T2 antitumor responses observed in naive and tumor-bearing mice. 2) To develop in vitro strategies that promote or amplify the induction of a tumor-specific T1 immune response and determine whether they improve efficacy in naive and tumor-bearing mice. 3) To develop in vivo strategies that promote the differentiation of tumor-specific T1 T cells and determine whether they improve therapeutic efficacy in naive and tumor-bearing mice.