This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Tsuda, N. Articles by Ioannides, C. G. Search for Related Content PubMed PubMed Citation Articles by Tsuda, N. Articles by Ioannides, C. G.

Taxol Increases the Amount and T Cell–Activating Ability of Self-Immune Stimulatory Multimolecular Complexes Found in Ovarian Cancer Cells

Departments of ¹ Gynecologic Oncology, ² Gastrointestinal Medical Oncology, and ³ Immunology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas; ⁴ Department of Immunology, Kurume University School of Medicine, Kurume, Japan; ⁵ Department of Pharmacology, Merck & Co, Boston, Massachusetts; Departments of ⁶ Microbiology and ⁷ Medicine, Division of Infectious Diseases and ⁸ Emerging Pathogens Institute, Mt. Sinai School of Medicine, New York, New York; and ⁹ Hillman Cancer Center, University of Pittsburgh, Cancer Institute, Pittsburgh, Pennsylvania

Requests for reprints: Constantin G. Ioannides, Department of Gynecologic Oncology, Unit 304, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-792-2849; Fax: 713-745-5099; E-mail: cioannid{at}mdanderson.org.

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- 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-, 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. [Cancer Res 2007;67(17):8378–87]