1) CCL17 is chemokine involved in recruitment of Th2-type cytokine-producing immune cells, including Tregs, acting through its receptor CCR4. Here, we found that primary breast cancer is responsible for the initial control of of metastasis. It induces production of CCL17 in the lungs lungs to facilitate co-recruitment of CCR4+ breast cancer cell and Tregs. The co-infiltration of Tregs is to protect the metastasizing cancer cells from NK cells in the lungs (see AG000443-04). Utilizing in house developed strategies, such as chemotoxin that depletes CCR4+ cells (see AG000444-04), we demonstrate that the approaches that target any part of this pathway can successfully interfere with cancer metastasis. This is a first report on the importance of TARC/CCR4 axis in the metastatic spread of breast cancer (Olkhanud et al., 2009;2011). 2) Recently, we have found previously a novel mechanism that links pulmonary inflammation with breast cancer lung metastasis. We were among the first to demonstrate that breast cancer cells also utilize Thymic stromal lymphopoietin (TSLP, an IL-7-like type 1 cytokine that contributes to lymphoid development and promotes Th2-type allergic responses)to promote tumor progression and metastasis. The cancer-promoting activity of TSLP required CD4+ T cells to facilitate Th2-skewed immune responses whereas TSLP-stimulated dendritic cells had a negative effect on tumor growth. We propose that TSLP may be a cancer prognostic marker and that its targeting could have therapeutic potential (Biragyn &Leonard, Patent, pending). For example, the strategies that interfere with the expression of TSLP led to the dramatic decrease in tumor size and metastasis. 3) In this part of the work we wanted to test whether the inactivation of regulatory immune cells such as tBregs (the cells originally discovered in my laboratory) or suppressive factors (such as TARC and TSLP) would improve efficacy of our cancer vaccines. The first part of this work, the development of potent and simple cancer vaccines, has been successfully achieved. For example, we created chemokine-based novel vaccine strategy that was reported in several our papers (Biragyn et al. 1999;2001;2002, 2004;2007;Schiavo et al., 2006). The breadth of the chemokine-based vaccines are in their ability to efficiently utilize the MHC processing pathways to elicit CD4+ T helper and CD8+ T cell responses (Biragyn et al., 2006;Schiavo et al., 2006). As a result, we have created two chemokine-based vaccine for human use: 1) The vaccine that targets an embryonic antigen OFA-iLRP (a highly conserved the 37-kDa oncofetal immature laminin receptor, that is specifically and highly expressed in a number of human malignancies) and 2) The SPANX-B -targeting vaccine. SPANX-B (a sperm protein associated with the nucleus on the chromosome X B) is a novel antigen with unknown function. The preclinical study of the OFA-iLPR vaccine was completed and reported (Biragyn et al., 2007;Patent, pending) it is ready to be tested in human clinical trials. We also reported clinical efficacy of SPANX-B using healthy humans leukocytes. We found that humans contain detectable amounts of circulating SPANX-B -specific T cell precursors that could be readily expanded to generate both helper CD4+ T cells and cytolytic CD8+ T cells (Almanzar et al., 2009;Biragyn and Larionov, Patent, pending). Encouraged by these results, recently we started the second phase of the work to test the role of regulatory immune cells, such as tBregs and Tregs, or suppressive factors (TSLP and CCL17) in the modulation of vaccine responses. 4) Alzheimer's disease (AD) is an incurable and progressive neurodegenerative senile disorder associated with the brain accumulation of Ab plaques. Although vaccines that reduce Ab plaques can control AD, the rationale for their use at the onset of the disease remains debatable. Old humans and mice usually respond ppoorly to vaccines due to presumably age-related immunological impairments. Here, we report that, by modifying vaccines, the poor responsiveness of old mice can be reversed. Unlike Ab peptide vaccine, DNA immunizations with the amino-terminal Ab(1-11) fragment exposed on the surface of HBsAg particles elicit high levels of anti-Ab antibody both in young and old mice. Importantly, in AD model 3xTgAD mice, the vaccine reduced Ab plaques, ameliorated cognitive impairments and, surprisingly, significantly increased life span. Hence, we propose that vaccines targeting Ab(1-11) can efficiently combat AD-induced pathological alterations and provide survival benefit in patients with AD (Olkhanud et al., 2011, submitted).
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