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

Abstract

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 mitoticphase 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]

Intraepithelial CD8-positive T lymphocytes predict survival for patients with serous stage III ovarian carcinomas: relevance of clonal selection of T lymphocytes

“…The presence of high numbers of intraepithelial, but not stromal, CD8-positive T lymphocytes was of uni-and multivariate prognostic benefit for stage III ovarian cancer patients, especially in the large subgroup of patients receiving adjuvant paclitaxel/carboplatin therapy. Interestingly, Tsuda et al, 2007 showed that Taxol stimulates the immunogenic potential of CD8-positive T cells in vitro, an effect that may be further exploited in current therapeutic studies (Disis et al, 2002).…”

<em>nab</em>-Paclitaxel as a potential partner with checkpoint inhibitors in solid tumors

“…A greater influx of tumor-infiltrating lymphocytes in breast cancer tumors has been correlated with a better response to chemotherapy 59,61. Paclitaxel may be a particularly strong immunostimulant, as it is able to both activate CD8 + T cells and reduce immunosuppressive cells, such as regulatory T cells 62,63. Docetaxel has been shown to increase CD8 + T-cell production of IFNγ (a stimulator of tumor-cell killing), but docetaxel does not appear to inhibit the suppressor function of regulatory T cells 64.…”

Immune contexture and histological response after neoadjuvant chemotherapy predict clinical outcome of lung cancer patients

“…If chemotherapy drugs have been designed to induce tumor cell death, 11 they also can boost or hamper protective immune responses by modifying the composition and function of the tumor immune contexture. [11][12][13][14] The aim of the present study was to characterize the tumor and immune compartments of NSCLC patients treated with neoadjuvant chemotherapy and evaluate their association with clinical outcome.…”