Immunologic memory involving CD8+ T cells is a hallmark of an adaptive antigen (Ag)-specific immune response and constitutes a critical component of protective immunity. Designing approaches that enhance long-term T cell memory would, for the most part, fortify vaccines and enhance host protection against infectious diseases and, perhaps, cancer immunotherapy. A better understanding of the cellular programs involved in the Ag-specific T-cell response has led to new approaches that target the magnitude and quality of the memory T-cell response. We have shown that T cells from TCR (T-cell receptor) transgenic mice for the nucleoprotein of influenza virus NP68 exhibit the distinct phases - priming, expansion, contraction, and memory - of an Ag-specific T-cell response when exposed in vitro to the cognate peptide. Saracatinib, a specific inhibitor of Src family kinases, administered at low doses during the expansion or contraction phases, increased CD62Lhigh/CD44high central memory CD8+ T cells and IFN-gamma production but suppressed immunity when added during the priming phase. These effects by saracatinib were not accompanied by the expected decline of Src family kinases but were accompanied by Akt-mammalian target of rapamycin suppression and/or mediated via another pathway. Increased central memory cells by saracatinib were recapitulated in mice using a poxvirus-based influenza vaccine, thus underscoring the importance of dose and timing of the inhibitor in the context of memory T-cell differentiation. Finally, vaccine plus saracatinib treatment showed better protection against tumor challenge. The immune-potentiating effects on CD8+ T cells by a low dose of saracatinib might afford better protection from pathogens or cancer when combined with vaccine.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC010970-05
Application #
8552905
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2012
Total Cost
$937,885
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Vandeveer, Amanda J; Fallon, Jonathan K; Tighe, Robert et al. (2016) Systemic Immunotherapy of Non-Muscle Invasive Mouse Bladder Cancer with Avelumab, an Anti-PD-L1 Immune Checkpoint Inhibitor. Cancer Immunol Res 4:452-62
Fallon, Jonathan; Tighe, Robert; Kradjian, Giorgio et al. (2014) The immunocytokine NHS-IL12 as a potential cancer therapeutic. Oncotarget 5:1869-84
Tucker, Jo A; Jochems, Caroline; Boyerinas, Benjamin et al. (2014) Identification and characterization of a cytotoxic T-lymphocyte agonist epitope of brachyury, a transcription factor involved in epithelial to mesenchymal transition and metastasis. Cancer Immunol Immunother 63:1307-17
Schlom, Jeffrey; Hodge, James W; Palena, Claudia et al. (2014) Therapeutic cancer vaccines. Adv Cancer Res 121:67-124
Takai, Shinji; Schlom, Jeffrey; Tucker, Joanne et al. (2013) Inhibition of TGF-?1 signaling promotes central memory T cell differentiation. J Immunol 191:2299-307
Takai, Shinji; Sabzevari, Helen; Farsaci, Benedetto et al. (2012) Distinct effects of saracatinib on memory CD8+ T cell differentiation. J Immunol 188:4323-33
Bonmassar, Laura; Fossile, Emanuela; Scoppola, Alessandro et al. (2010) Detection of circulating tumor cells is improved by drug-induced antigen up-regulation: preclinical and clinical studies. Anticancer Res 30:4721-30
Hance, Kenneth W; Rogers, Connie J; Zaharoff, David A et al. (2009) The antitumor and immunoadjuvant effects of IFN-alpha in combination with recombinant poxvirus vaccines. Clin Cancer Res 15:2387-96
Wansley, Elizabeth K; Chakraborty, Mala; Hance, Kenneth W et al. (2008) Vaccination with a recombinant Saccharomyces cerevisiae expressing a tumor antigen breaks immune tolerance and elicits therapeutic antitumor responses. Clin Cancer Res 14:4316-25
Zeytin, Hasan; Reali, Eva; Zaharoff, David A et al. (2008) Targeted delivery of murine IFN-gamma using a recombinant fowlpox virus: NK cell recruitment to regional lymph nodes and priming of tumor-specific host immunity. J Interferon Cytokine Res 28:73-87