Chemotherapy broadens the range of tumor antigens seen by cytotoxic CD8(+) T cells in vivo.
Cytotoxic chemotherapies may expose the immune system to high levels of tumor antigens and expand the CD8(+) 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 IFNγ 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.
Immunology and Cancer Group, School of Biomedical Sciences, Curtin University, Kent St., Bentley, Perth, WA, 6102, Australia.
Connie
C
Jackaman
David
D
Majewski
Simon A
SA
Fox
Anna K
AK
Nowak
Delia J
DJ
Nelson
D000818:Animals; D017951:Antigen Presentation / Q000187:drug effects; D000951:Antigens, Neoplasm / Q000276:immunology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D000939:Epitopes / Q000276:immunology; D005260:Female; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology; D007376:Interleukin-2 / Q000276:immunology; D008654:Mesothelioma / Q000188:drug therapy* / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010047:Ovalbumin / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology*; D014162:Transfection / Q000379:methods; D000093542:Gemcitabine
D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D000939:Epitopes; D015395:Histocompatibility Antigens Class I; D007376:Interleukin-2; D003841:Deoxycytidine; D007371:Interferon-gamma; D010047:Ovalbumin; D002945:Cisplatin; D000093542:Gemcitabine