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.
| Messenheimer, David J; Jensen, Shawn M; Afentoulis, Michael E et al. (2017) Timing of PD-1 Blockade Is Critical to Effective Combination Immunotherapy with Anti-OX40. Clin Cancer Res 23:6165-6177 |
| Feng, Zipei; Puri, Sachin; Moudgil, Tarsem et al. (2015) Multispectral imaging of formalin-fixed tissue predicts ability to generate tumor-infiltrating lymphocytes from melanoma. J Immunother Cancer 3:47 |
| Church, Sarah E; Jensen, Shawn M; Antony, Paul A et al. (2014) Tumor-specific CD4+ T cells maintain effector and memory tumor-specific CD8+ T cells. Eur J Immunol 44:69-79 |
| Winter, Hauke; Fox, Bernard A; Rüttinger, Dominik (2014) Future of cancer vaccines. Methods Mol Biol 1139:555-64 |
| Jensen, Shawn M; Twitty, Christopher G; Maston, Levi D et al. (2012) Increased frequency of suppressive regulatory T cells and T cell-mediated antigen loss results in murine melanoma recurrence. J Immunol 189:767-76 |
| Church, Sarah E; Jensen, Shawn M; Twitty, Christopher G et al. (2011) Multiple vaccinations: friend or foe. Cancer J 17:379-96 |
| Bedognetti, Davide; Balwit, James M; Wang, Ena et al. (2011) SITC/iSBTc Cancer Immunotherapy Biomarkers Resource Document: online resources and useful tools - a compass in the land of biomarker discovery. J Transl Med 9:155 |
| Winter, Hauke; van den Engel, Natasja K; Rusan, Margareta et al. (2011) Active-specific immunotherapy for non-small cell lung cancer. J Thorac Dis 3:105-14 |
| Fox, Bernard A; Schendel, Dolores J; Butterfield, Lisa H et al. (2011) Defining the critical hurdles in cancer immunotherapy. J Transl Med 9:214 |
| Twitty, Christopher G; Jensen, Shawn M; Hu, Hong-Ming et al. (2011) Tumor-derived autophagosome vaccine: induction of cross-protective immune responses against short-lived proteins through a p62-dependent mechanism. Clin Cancer Res 17:6467-81 |
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