Cancer vaccines and adoptive T cell transfer approaches hold promise for cancer treatment and the prevention of tumor recurrence. Whereas these therapies often increase tumor-specific T cell levels, they are often ineffective in inducing potent effector T cells and long-lived, functional memory T cells that can mediate long-term tumor suppression. This ineffective generation of tumor-specific memory T cells is possibly due to a lack of stimulation by inflammatory mediators derived from innate immune cells. Type I Interferons, including IFN-?, are inflammatory mediators induced by pathogen-derived molecules and activate innate and adaptive immune cells including CD8 T cells. Our preliminary results in a unique model system demonstrate that systemic levels of IFN-?, similar to those found during acute viral infection, greatly enhance the vaccination-induced generation of gp100-specific effector and memory CD8 T cells with anti- melanoma activity. In addition, our preliminary data show that IFN-? exerts this activity through multiple mechanisms during distinct phases of the T cell response. Our long-term goals are to understand the regulation of generation and maintenance of tumor-specific memory CD8 T cells and learn to enhance them. This proposal is in direct response to the NIH Program Announcement PA-07-255 "Memory T lymphocytes in Cancer Immunology" and will focus on signals throughout the immune response that culminate into the generation and long-term maintenance of therapeutic tumor-specific memory CD8 T cells. The overall objective of this proposal is to understand how IFN-? promotes anti-tumor CD8 T cell responses through mechanistic dissection of its effects on T cells and the host environment. Our central hypothesis is that IFN-? enhances the in vivo and ex vivo generation of long-lived, tumor-specific memory CD8 T cells through direct effects on T cells during the early priming/expansion phase and through host-derived IL-15 and CD27/CD70 signals during subsequent memory T cell differentiation and maintenance. This hypothesis will be tested by pursuing the following three specific aims: 1) Determine the contribution of IFN-? during the different phases of the vaccination/IFN-?-induced, tumor-specific CD8 T cell response;2) Identify the molecular mechanisms underlying the IFN-?-induced in vivo generation of tumor-specific memory CD8 T cells;3) Determine whether IFN-? can promote the ex vivo generation of tumor-specific CD8 T cells that have characteristics of therapeutic anti-tumor memory T cells in vivo. Overall, the proposed studies will elucidate the mechanisms underlying IFN-?-induced anti-tumor immunity and will directly lead to the development of more effective cancer therapies.
Some cancer therapies attempt to utilize and enhance the immune system's natural ability to eliminate tumors by generating tumor-specific T cells. We have found that IFN-?, currently used to treat melanoma patients, promotes the generation of tumor-specific memory T cells. This proposal attempts to better determine the mechanism underlying this activity of IFN-? in order to harness its activity to effectively eliminate tumors, guiding the design of future cancer immunotherapies.
|Singh, Manisha; Khong, Hiep; Dai, Zhimin et al. (2014) Effective innate and adaptive antimelanoma immunity through localized TLR7/8 activation. J Immunol 193:4722-31|
|Hailemichael, Yared; Overwijk, Willem W (2014) Cancer vaccines: Trafficking of tumor-specific T cells to tumor after therapeutic vaccination. Int J Biochem Cell Biol 53:46-50|
|Liu, Chengwen; Peng, Weiyi; Xu, Chunyu et al. (2013) BRAF inhibition increases tumor infiltration by T cells and enhances the antitumor activity of adoptive immunotherapy in mice. Clin Cancer Res 19:393-403|
|Hailemichael, Yared; Dai, Zhimin; Jaffarzad, Nina et al. (2013) Persistent antigen at vaccination sites induces tumor-specific CD8ýýý T cell sequestration, dysfunction and deletion. Nat Med 19:465-72|
|Sikora, Andrew G; Hailemichael, Yared; Overwijk, Willem W (2012) Conference scene: immune effector mechanisms in tumor immunity. Immunotherapy 4:141-3|
|Liu, Chengwen; Lewis, Carol M; Lou, Yanyan et al. (2012) Agonistic antibody to CD40 boosts the antitumor activity of adoptively transferred T cells in vivo. J Immunother 35:276-82|