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Blood, Vol. 93 No. 6 (March 15), 1999:
pp. 1831-1837
RAPID COMMUNICATION
Cytokine-Based Tumor Cell Vaccine Is Equally Effective Against
Parental and Isogenic Multidrug-Resistant Myeloma Cells: The Role
of Cytotoxic T Lymphocytes
Alexander A. Shtil,
Joel G. Turner,
John Durfee,
William S. Dalton, and
Hua Yu
From the Clinical Investigations Program and Immunology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL; and the
Department of Internal Medicine and the Department of Medical
Microbiology and Immunology, University of South Florida College of
Medicine, Tampa, FL.
Tumor cells that survive initial courses of chemotherapy may do so
by acquiring a multidrug-resistant phenotype. This particular mechanism
of drug resistance may also confer resistance to physiological effectors of apoptosis that could potentially reduce the efficacy of
immune therapies that use these pathways of cell death. We have
previously demonstrated high efficacy for a cytokine-based tumor cell
vaccine in a murine MPC11 myeloma model. In the present study, the
effects of this vaccination were compared in MPC11 cells and their
isogenic sublines selected for mdr1/P-glycoprotein (Pgp)-mediated multidrug resistance (MDR). Immunization with MPC11 cells expressing granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-12 (IL-12) led to long-lasting protection of
mice against subcutaneous (sc) challenge with both
parental cells or their MDR variants. Similarly, immunization with
GM-CSF/IL-12-transfected MDR sublines caused rejection of
transplantation of both parental cells and the MDR sublines. Whereas
MPC11 cells and their MDR variants were resistant to APO-1/CD95/Fas
ligand, the immunization generated potent granzyme B/perforin-secreting
cytotoxic T lymphocytes (CTLs) that were similarly effective against
both parental and isogenic MDR cells. We conclude that MDR mediated by
mdr1/Pgp did not interfere with lysis by pore-forming CTLs.
Immunotherapy based on pore-forming CTLs may be an attractive approach
to the treatment of drug-resistant myeloma.
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