Details

Autor(en) / Beteiligte

• Jackaman, Connie
• Majewski, David
• Fox, Simon A
• Nowak, Anna K
• Nelson, Delia J

Titel

Chemotherapy broadens the range of tumor antigens seen by cytotoxic CD8 super(+) T cells in vivo

Ist Teil von

• Cancer Immunology, Immunotherapy, 2012-12, Vol.61 (12), p.2343-2356

Erscheinungsjahr

2012

Link zum Volltext

Quelle

SpringerLink (Online service)

Beschreibungen/Notizen

• Cytotoxic chemotherapies may expose the immune system to high levels of tumor antigens and expand the CD8 super(+) T-cell response to include weak or subdominant antigens. Here, we evaluated the in vivo CTL response to tumor antigens using a murine mesothelioma tumor cell line transfected with a neotumor antigen, ovalbumin, that contains a known hierarchy of epitopes for MHC class I molecules. We show that as tumors progress, effector CTLs are generated in vivo that focus on the dominant epitope SIINFEKL, although a weak response was seen to one (KVVRFDKL) subdominant epitope. These CTLs did not prevent tumor growth. Cisplatin treatment slowed tumor growth, slightly improved in vivo SIINFEKL presentation to T cells and reduced SIINFEKL-CTL activity. However, the CTL response to KVVRFDKL was amplified, and a response to another subdominant epitope, NAIVFKGL, was revealed. Similarly, gemcitabine cured most mice, slightly enhanced SIINFEKL presentation, reduced SIINFEKL-CTL activity yet drove a significant CTL response to NAIVFKGL, but not KVVRFDKL. These NAIVFKGL-specific CTLs secreted IFN gamma and proliferated in response to in vitro NAIVFKGL stimulation. IL-2 treatment during chemotherapy refocused the response to SIINFEKL and simultaneously degraded the cisplatin-driven subdominant CTL response. These data show that chemotherapy reveals weaker tumor antigens to the immune system, a response that could be rationally targeted. Furthermore, while integrating IL-2 into the chemotherapy regimen interfered with the hierarchy of the response, IL-2 or other strategies that support CTL activity could be considered upon completion of chemotherapy.