Taxol increases the amount and T cell activating ability of self-immune stimulatory multimolecular complexes found in ovarian cancer cells.
It has been proposed that chemotherapy enhances tumor antigen (TA)-specific immunity. The molecular form of TA from ovarian tumor that activates cellular immunity is unknown. We report here identification of a novel molecular form of immunogenic TA for CD8(+) cells named self-immune stimulatory multimolecular complexes (ISMMC). ISMMC consist of a molecular complex of polyosome/ribosome-bound ubiquitinated nascent HER-2 polypeptides. This complex is chaperoned by heat shock protein Gp96, which mediates ISMMC uptake by antigen-presenting cells through the scavenger receptor CD91. RNAs in ISMMC stimulate immature dendritic cells to secrete interleukin 12 and induce IFN-gamma in peripheral blood mononuclear cells. ISMMC dissociate, retrotranslocate from the lysosome to cytoplasm, and are processed to peptides by the proteasome. At subpharmacologic doses, Taxol increased the amount of ISMMC by three to four times and modified their composition by inducing the attachment of cochaperones of HSP70, such as the mitotic-phase phosphoprotein 11J. On a total protein basis, Taxol induced ISMMC, expanded more CD8(+) cells, activated more CD56(+) NKG2D(+) cells to produce IFN-gamma, and were more potent inducers of high T-cell receptor density Perforin(+) cells than native ISMMC and peptide E75. Elucidation of the composition of ISMMC and identification of adducts formed by Taxol should be important for developing molecular cancer vaccines.
Tsuda
Naotake
N
Department of Gynecologic Oncology, The University of Texas M D Anderson Cancer Center, Houston, TX 77030, USA.
Chang
David Z
DZ
Mine
Takashi
T
Efferson
Clay
C
García-Sastre
Adolfo
A
Wang
Xinhui
X
Ferrone
Soldano
S
Ioannides
Constantin G
CG
D000936:Antigen-Antibody Complex / Q000187:drug effects / Q000276:immunology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D018664:Interleukin-12 / Q000378:metabolism; D007958:Leukocyte Count; D008213:Lymphocyte Activation / Q000187:drug effects*; D046912:Multiprotein Complexes / Q000187:drug effects* / Q000276:immunology; D010051:Ovarian Neoplasms / Q000276:immunology* / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology*; D010446:Peptide Fragments / Q000378:metabolism; D011132:Polyribosomes / Q000187:drug effects; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000737:chemistry / Q000378:metabolism; D012270:Ribosomes / Q000187:drug effects / Q000502:physiology; D013601:T-Lymphocytes / Q000166:cytology* / Q000187:drug effects*; D014407:Tumor Cells, Cultured; D025801:Ubiquitin / Q000378:metabolism