Prolonging microtubule dysruption enhances the immunogenicity of chronic lymphocytic leukaemia cells

• Published in: Clinical and experimental immunology 2009-11, Vol.158 (2), p.186-198
• Main Authors: Shaha, S.P, Tomic, J, Shi, Y, Pham, T, Mero, P, White, D, He, L, Baryza, J.L, Wender, P.A, Booth, J.W, Spaner, D.E
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Analytical, structural and metabolic biochemistry; Antigens, CD - metabolism; Antineoplastic Agents, Phytogenic - pharmacology; Biological and medical sciences; Bryostatins - pharmacology; cancer vaccines; Cell Survival - drug effects; chemotherapy; chronic lymphocytic leukaemia; Clinical Trials, Phase IV as Topic - methods; co-stimulatory molecules; Cytotoxicity, Immunologic; Drug Interactions; Enzyme Activators - pharmacology; Female; Fundamental and applied biological sciences. Psychology; Hematologic and hematopoietic diseases; Humans; Immunophenotyping; Leukemia, Lymphocytic, Chronic, B-Cell - immunology; Leukemia, Lymphocytic, Chronic, B-Cell - pathology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Lymphocyte Activation - drug effects; Lymphocyte Culture Test, Mixed; Male; Medical sciences; Microtubules - drug effects; Middle Aged; Phorbol 12,13-Dibutyrate - pharmacology; Phorbol Esters - pharmacology; Protein Kinase C - physiology; Signal Transduction - drug effects; Toll-like receptors; Translational Studies; Tubulin Modulators - pharmacology; Tumor Necrosis Factor-alpha - biosynthesis; Vincristine - pharmacology
• ISSN: 0009-9104; 1365-2249
• DOI: 10.1111/j.1365-2249.2009.04003.x

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-κB) 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.