Rescuing melanoma epitope-specific cytolytic T lymphocytes from activation-induced cell death, by SP600125, an inhibitor of JNK: implications in cancer immunotherapy.
Activation-induced cell death (AICD) as well as programmed cell death (PCD) serve to control the expansion of activated T cells to limit untoward side effects of continued effector responses by T cells and to maintain homeostasis. AICD of T cells in tumor immunotherapy can be counterproductive particularly if the activated T cells undergo apoptotic death after the very first secondary encounter of the specific epitope. We examined the extent to which tumor epitope-specific CTLs that are activated and expanded in an in vitro-matured dendritic cell-based primary stimulation protocol undergo AICD following their first secondary encounter of the cognate epitope. Using the MART-1(27-35) epitope as a prototype vaccine epitope, we also examined whether these CTLs could be rescued from AICD. Our results demonstrate that a substantial fraction of MART-1(27-35) epitope-specific primary CTLs undergo AICD upon the very first secondary encounter of the cognate epitope. The AICD in these CTLs is neither caspase dependent nor is it triggered by the extrinsic death signaling pathways (Fas, TNFR, etc.). These CTLs, interestingly, could be rescued from AICD by the JNK inhibitor, SP600125. We also found that SP600125 interferes with their IFN-gamma response but does not block their cytolytic function. The rescued CTLs, however, regain their capacity to synthesize IFN-gamma if continued in culture without the inhibitor. These observations have implications in tumor immunotherapy and in further studies for regulation of AICD in CTLs.
Mehrotra
Shikhar
S
Division of Hematology/Oncology, Department of Medicine, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030, USA.
Chhabra
Arvind
A
Chattopadhyay
Subhasis
S
Dorsky
David I
DI
Chakraborty
Nitya G
NG
Mukherji
Bijay
B
D000873:Anthracenes / Q000494:pharmacology*; D017951:Antigen Presentation; D016923:Cell Death / Q000187:drug effects / Q000276:immunology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D018920:Coculture Techniques; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000939:Epitopes / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D016056:Immunodominant Epitopes / Q000276:immunology; D016219:Immunotherapy, Adoptive / Q000379:methods; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D019409:Interleukin-15 / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D008545:Melanoma / Q000201:enzymology / Q000276:immunology / Q000628:therapy*; D009363:Neoplasm Proteins / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology* / Q000201:enzymology / Q000276:immunology*
D000873:Anthracenes; D004791:Enzyme Inhibitors; D000939:Epitopes; D018984:Epitopes, T-Lymphocyte; D016056:Immunodominant Epitopes; D019409:Interleukin-15; C105787:MART-1-Melan-A(27-35) epitope; D009363:Neoplasm Proteins; C432165:pyrazolanthrone; D007371:Interferon-gamma; D048031:JNK Mitogen-Activated Protein Kinases