Effective anti-tumor immunity requires the generation and persistence of functional, high avidity tumor-specific effector and memory T cells. Among the critical factors that often control this response is the activation/differentiation state of the relevant effector T-cells. We have made the singular observation that IL- 12 conditioning during in vitro priming is able to promote the acquisition of a central memory (Tcm) like phenotype in antigen-specific T cells. These """"""""early activated"""""""" T (TEA) cells are characterized by increased expression of lymph node (LN) homing receptors, robust proliferation in vitro, an augmented survival, and increased anti-tumor activity in vivo. We have also recently observed that cyclophosphamide (CTX) preconditioning induces expansion of immature DCs mainly in the peripheral blood during the rebound phase which is associated with highly effective anti-tumor responses in vivo. With an interest in capitalizing on the combined potential of these observations, we hypothesize that the enhanced survival and function of IL- 12 pre-conditioned TEA cells will result in the generation of more effective anti-tumor immunity when combined with a surging frequency of circulating DCs. To test this hypothesis we propose to define how IL-12 pre-conditioning enhances T-cell survival and function (looking at co-stimulation signature, survival signaling, and impact on functional avidity) and define the TEA cell response to antigen presentation in a DC rich environment (looking specifically at the contribution of secondary lymphoid compartments. The ability to understand and harness the combined potential of early activated T cell generation and robust circulating DC induction could serve to synergistically augment in the generation of an effective anti-tumor response in vivo. The two year ARRA funding mechanism will allow us to address the first aspect of this goal by defining how IL-12 conditioning enhances antigen experienced T-cell survival and function.

Public Health Relevance

Our focus is to generate new and more effective ways to treat cancer. Understanding the mechanisms behind the generation of effective anti-tumor immune responses will provide the scientific basis for novel clinical strategies leading to the design of more effective immunotherapy protocols.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Cancer Immunopathology and Immunotherapy Study Section (CII)
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Mccarthy, Susan A
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Medical University of South Carolina
Schools of Medicine
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Rubinstein, Mark P; Cloud, Colleen A; Garrett, Tracy E et al. (2012) Ex vivo interleukin-12-priming during CD8(+) T cell activation dramatically improves adoptive T cell transfer antitumor efficacy in a lymphodepleted host. J Am Coll Surg 214:700-7; discussion 707-8
Salem, Mohamed L; Al-Khami, Amir A; El-Nagaar, Sabry A et al. (2012) Kinetics of rebounding of lymphoid and myeloid cells in mouse peripheral blood, spleen and bone marrow after treatment with cyclophosphamide. Cell Immunol 276:67-74
Díaz-Montero, C Marcela; Naga, Osama; Zidan, Abdel-Aziz A et al. (2011) Synergy of brief activation of CD8 T-cells in the presence of IL-12 and adoptive transfer into lymphopenic hosts promotes tumor clearance and anti-tumor memory. Am J Cancer Res 1:882-96
Salem, Mohamed L; Al-Khami, Amir A; El-Naggar, Sabry A et al. (2010) Cyclophosphamide induces dynamic alterations in the host microenvironments resulting in a Flt3 ligand-dependent expansion of dendritic cells. J Immunol 184:1737-47
Salem, Mohamed L; El-Naggar, Sabry A; Cole, David J (2010) Cyclophosphamide induces bone marrow to yield higher numbers of precursor dendritic cells in vitro capable of functional antigen presentation to T cells in vivo. Cell Immunol 261:134-43
Salem, Mohamed Labib; Cole, David J (2010) Dendritic cell recovery post-lymphodepletion: a potential mechanism for anti-cancer adoptive T cell therapy and vaccination. Cancer Immunol Immunother 59:341-53
Salem, Mohamed L; Demcheva, Marina; Gillanders, William E et al. (2010) Poly-N-acetyl glucosamine gel matrix as a non-viral delivery vector for DNA-based vaccination. Anticancer Res 30:3889-94
Rubinstein, M P; Salem, M L; Kadima, A N et al. (2009) Loss of T cell-mediated antitumor immunity after construct-specific downregulation of retrovirally encoded T-cell receptor expression in vivo. Cancer Gene Ther 16:171-83
Diaz-Montero, C Marcela; Salem, Mohamed Labib; Nishimura, Michael I et al. (2009) Increased circulating myeloid-derived suppressor cells correlate with clinical cancer stage, metastatic tumor burden, and doxorubicin-cyclophosphamide chemotherapy. Cancer Immunol Immunother 58:49-59
Salem, Mohamed L; Díaz-Montero, C Marcela; Al-Khami, Amir A et al. (2009) Recovery from cyclophosphamide-induced lymphopenia results in expansion of immature dendritic cells which can mediate enhanced prime-boost vaccination antitumor responses in vivo when stimulated with the TLR3 agonist poly(I:C). J Immunol 182:2030-40

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