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 AG000443-05). Utilizing in house developed strategies, such as chemotoxin that depletes CCR4+ cells (see AG000444-05), 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). Here, we investigated whether TARC-chemotoxin can also augment cancer vaccine responses. Although this is ongoing study, our preliminary data indicate that CD8+ T cell responses to our cancer vaccines, such as MIP3a-OFA and MIP3a-gp100, can be enhanced by transient depletion of CCR4+ Tregs with TARC-chemotoxin. 2) Recently, we have found previously unknown 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 (Olkhanud et al., 2011;and see AG000443-05). 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. The study had to prematurely stopped due to departure of a postdoc, but we plan to continue it as soon as we hire a new fellow. 3) In this part of the work we wanted to inactivate regulatory immune cells such as tBregs (the cells originally discovered in my laboratory, see AAG000443-05) in order to improve outcome and vaccine responses in tumor-bearing mice. In previous reports, we described successful accomplishments of the first part of this study, the development of potent and simple cancer vaccines. We created a number of chemokine-based novel vaccines for human use (Biragyn et al. 1999;2001;2002, 2004;2007;Schiavo et al., 2006). For example, 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). 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). Note: The breadth of our chemokine-based vaccines is 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). The second phase of the study is 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. Due to a departure of my fellow, we had to temporarily stop this part of the work. However, we plan to resume the study in near future. 3) Recently we completed our study on the therapeutic use and mechanism of resveratrol (RSV), a polyphenol originally extracted from red wine). We demonstrate that despite the aggressive nature of 4T1 breast cancer in mice, RSV can efficiently block its escape and metastasis. The mechanism of this process was that RSV inhibited the generation and activity of tBregs. As a result, RSV-treated mice elicited cancer-neutralizing effector CD8+ T cells due to the loss of suppressive activity of tBregs and their inability to induce conversion of Tregs. The manuscript describing these findings will be submitted for publication in November of 2012 (Lee-Chang et al., 2012). 4) We also successfully completed our study on the use of immunostimulatory CpG-containing oligonucleotides (CpG) to inactivate tBregs and block cancer escape. To circumvent the lack of targeted delivery methods for CpG for in vivo use, we devised CXCL13 chemokine-based strategy (see AG000443-05). Using mice with 4T1 breast cancer, we demonstrate that CXCL13-mediated delivery of CpG not only inactivates tBregs, but also induces antitumor responses of conventional B cells. As a result, breast cancer metastasis was blocked in CXCL13/CpG-treated tumor-bearing mice by inducing antitumor effector CD8+ T cells. The paper describing these findings has been submitted for publication (Bodogai et al., 2012). 5) 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 poorly to vaccines due to presumably age-related immunological impairments. Here, to circumvent these problems and to develop vaccine designed for elderly people, we created a novel vaccine formulation for AD. Using our AD vaccine, we demonstrate that the old age-related poor vaccine response is reversible in old mice. Unlike traditional Ab peptide vaccines, 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., 2012).

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIAAG000770-09
Application #
8552472
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
9
Fiscal Year
2012
Total Cost
$212,770
Indirect Cost
Name
National Institute on Aging
Department
Type
DUNS #
City
State
Country
Zip Code
Freeman, David W; Noren Hooten, Nicole; Eitan, Erez et al. (2018) Altered Extracellular Vesicle Concentration, Cargo, and Function in Diabetes. Diabetes 67:2377-2388
Kim, Kyoung Mi; Noh, Ji Heon; Bodogai, Monica et al. (2018) SCAMP4 enhances the senescent cell secretome. Genes Dev 32:909-914
Biragyn, Arya; Ferrucci, Luigi (2018) Gut dysbiosis: a potential link between increased cancer risk in ageing and inflammaging. Lancet Oncol 19:e295-e304
Eitan, Erez; Green, Jamal; Bodogai, Monica et al. (2017) Age-Related Changes in Plasma Extracellular Vesicle Characteristics and Internalization by Leukocytes. Sci Rep 7:1342
Kim, Kyoung Mi; Noh, Ji Heon; Bodogai, Monica et al. (2017) Identification of senescent cell surface targetable protein DPP4. Genes Dev 31:1529-1534
Lu, Daoyuan; Cai, Huan; Park, Sung-Soo et al. (2017) Correction for Lu et al., ""Nuclear GIT2 Is an ATM Substrate and Promotes DNA Repair"". Mol Cell Biol 37:
Biragyn, Arya; Aliseychik, Maria; Rogaev, Evgeny (2017) Potential importance of B cells in aging and aging-associated neurodegenerative diseases. Semin Immunopathol 39:283-294
Lee-Chang, Catalina; Bodogai, Monica; Moritoh, Kanako et al. (2016) Aging Converts Innate B1a Cells into Potent CD8+ T Cell Inducers. J Immunol 196:3385-97
Lee-Chang, Catalina; Bodogai, Monica; Moritoh, Kanako et al. (2014) Accumulation of 4-1BBL+ B cells in the elderly induces the generation of granzyme-B+ CD8+ T cells with potential antitumor activity. Blood 124:1450-9
Lee-Chang, Catalina; Bodogai, Monica; Martin-Montalvo, Alejandro et al. (2013) Inhibition of breast cancer metastasis by resveratrol-mediated inactivation of tumor-evoked regulatory B cells. J Immunol 191:4141-51

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