Prolonging microtubule dysruption enhances the immunogenicity of chronic lymphocytic leukaemia cells.
Cytotoxic chemotherapies do not usually mediate the expression of an immunogenic gene programme in tumours, despite activating many of the signalling pathways employed by highly immunogenic cells. Concomitant use of agents that modulate and complement stress-signalling pathways activated by chemotherapeutic agents may then enhance the immunogenicity of cancer cells, increase their susceptibility to T cell-mediated controls and lead to higher clinical remission rates. Consistent with this hypothesis, the microtubule inhibitor, vincristine, caused chronic lymphocytic leukaemia (CLL) cells to die rapidly, without increasing their immunogenicity. Protein kinase C (PKC) agonists (such as bryostatin) delayed the death of vincristine-treated CLL cells and made them highly immunogenic, with increased stimulatory abilities in mixed lymphocyte responses, production of proinflammatory cytokines, expression of co-stimulatory molecules and activation of c-Jun N-terminal kinase (JNK), p38 and nuclear factor kappa B (NF-kappaB) signalling pathways. This phenotype was similar to the result of activating CLL cells through Toll-like receptors (TLRs), which communicate 'danger' signals from infectious pathogens. Use of PKC agonists and microtubule inhibitors to mimic TLR-signalling, and increase the immunogenicity of CLL cells, has implications for the design of chemo-immunotherapeutic strategies.
Shaha
S P
SP
Division of Molecular and Cellular Biology, Research Institute, Sunnybrook Health Sciences Center, Toronto, Canada.
Tomic
J
J
Shi
Y
Y
Pham
T
T
Mero
P
P
White
D
D
He
L
L
Baryza
J L
JL
Wender
P A
PA
Booth
J W
JW
Spaner
D E
DE
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD / Q000378:metabolism; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D054713:Bryostatins / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D017327:Clinical Trials, Phase IV as Topic / Q000379:methods; D003602:Cytotoxicity, Immunologic; D004347:Drug Interactions; D020536:Enzyme Activators / Q000494:pharmacology; D005260:Female; D006801:Humans; D016130:Immunophenotyping; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology* / Q000473:pathology; D008213:Lymphocyte Activation / Q000187:drug effects; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D008870:Microtubules / Q000187:drug effects*; D008875:Middle Aged; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D010703:Phorbol Esters / Q000494:pharmacology; D011493:Protein Kinase C / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D050257:Tubulin Modulators / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D014750:Vincristine / Q000494:pharmacology*
D015703:Antigens, CD; D000972:Antineoplastic Agents, Phytogenic; D054713:Bryostatins; D020536:Enzyme Activators; D010703:Phorbol Esters; D050257:Tubulin Modulators; D014409:Tumor Necrosis Factor-alpha; D015240:Phorbol 12,13-Dibutyrate; D014750:Vincristine; D011493:Protein Kinase C