Katrina Rey-McIntyre

University of Toronto, Toronto, Ontario, Canada

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Publications (3)13.35 Total impact

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    ABSTRACT: CD1d-restricted natural killer T (iNKT) cells have been shown to provide adjuvant activity against cancer by producing interferon (IFN)-γ. However, the role of invariant NKT (iNKT) cells in the tumor microenvironment has not yet been fully addressed. Our aim is to elucidate the antitumor effect of iNKT cells in the tumor microenvironment by using an intrathoracic murine malignant pleural mesothelioma model that we had previously developed and to provide pleural effusion as a good surrogate of the tumor microenvironment. We found that the number of iNKT cells increased dramatically in the pleural effusion after intrathoracic tumor cell injection at an earlier phase compared with accumulation of CD8 T cells. These iNKT cells showed increased expression of CD25 and increased ratio of cells positive for IFN-γ intracellular staining. iNKT cells sorted from pleural effusion of tumor burden mice produced larger amount of IFN-γ compared with naive mice. Mice pretreated in vivo with anti-CD1d-blocking Ab showed increased amount of pleural effusion and decreased ratio of total and effector-type CD8 T cells as well as decreased intracellular IFN-γ expression of CD8T-cell in the pleural effusion. In vivo administration of α-galactosylceramide (α-GalCer) showed prolonged survival associated with less pleural effusion and increased ratio of IFN-γ-positive iNKT cells and CD8 T cells in the pleural effusion. Therefore, this study suggests that iNKT cells accumulating in the tumor microenvironment play an antitumor effect by producing IFN-γ and enhancing subsequent CD8 T-cell response. Furthermore, in vivo administration of α-GalCer could suppress mesothelioma growth by activating iNKT cells.
    Journal of immunotherapy (Hagerstown, Md.: 1997) 08/2013; · 3.20 Impact Factor
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    ABSTRACT: Cancer immunotherapy has shown promising results when combined with chemotherapy. Blocking CTLA-4 signaling by monoclonal antibody between cycles of chemotherapy may inhibit cancer cell repopulation and enhance the antitumoral immune reaction, thus improve the efficacy of chemotherapy in mesothelioma. The impact of CTLA-4 blockade on the early stage of tumor development was evaluated in a subcutaneous murine mesothelioma model. CTLA-4 blocking antibody was administered following each cycle of chemotherapy, and monotherapy was included as controls. Antitumor effect was evaluated by tumor growth delay and survival of the animals. Tumor cell repopulation was quantified by bromodeoxyuridine incorporation and Ki67 by immunohistochemistry and/or flow cytometry. In vitro cell killing was determined by classic chromium-released assay, and reverse transcription PCR (RT-PCR) was carried out to determine the gene expression of associated cytokines. Anti-CTLA-4 monoclonal antibody was able to inhibit tumor growth at early stage of tumor development. Antitumor effect was achieved by administration of CTLA-4 blockade between cycles of chemotherapy. Tumor cell repopulation during the intervals of cisplatin was inhibited by CTLA-4 blockade. Anti-CTLA-4 therapy gave rise to an increased number of CD4 and CD8 T cells infiltrating the tumor. RT-PCR showed that the gene expression of interleukin IL-2, IFN-γ, granzyme B, and perforin increased in the tumor milieu. Blockade of CTLA-4 signaling showed effective anticancer effect, correlating with inhibiting cancer cell repopulation between cycles of chemotherapy and upregulating tumor-infiltrating T lymphocytes, cytokines, and cytolytic enzymes in a murine mesothelioma model.
    Molecular Cancer Therapeutics 05/2012; 11(8):1809-19. · 5.60 Impact Factor
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    ABSTRACT: Malignant pleural mesothelioma is a highly aggressive cancer with poor prognosis. We have previously demonstrated that regulatory T cells (Treg) depletion can impact tumor microenvironment when combined with chemotherapy. The aim of this study is to analyze the impact of Treg depletion on tumor cell repopulation during cycles of chemotherapy in a murine mesothelioma model. Tumor-bearing mice were treated with chemotherapy once weekly to mimic clinical settings and with PC61 to cause Treg depletion after each cycle of chemotherapy. Tumor cell repopulation was evaluated by BrdU labeling index with immunohistochemistry and flow cytometry, and Ki67 gene expression was determined by real-time reverse-transcribed polymerase chain reaction. The proportion of CD4+ CD25+Foxp3+ Tregs, CD4+, and CD8+ T cells in the tumor, spleen, draining lymph node, and peripheral blood from tumor-bearing mice was determined by using flow cytometry, and gene expression of activated T-cell-related cytokines was quantified by enzyme-linked immunosorbent assay and reverse-transcribed polymerase chain reaction. Tumor growth delay was achieved by cisplatin followed by PC61 or cyclophosphamide. The BrdU labeling index indicated that tumor cell repopulation between cycles of cisplatin was significantly inhibited by PC61. The CD4+CD25+Foxp3+ Tregs in tumor and lymphoid organs were almost completely depleted, whereas the CD4+ or CD8+ T cells did not change. PC61 after chemotherapy resulted in an increase of gene expression of interferon-γ, granzyme B, perforin, and IP-10, thus leading to tumor cell lysis in cytotoxic lymphocyte assay. Nevertheless, cell killing induced by cyclophosphamide combined with cisplatin was due to cytotoxicity rather than specific immune response. Treg depletion between cycles of chemotherapy could improve the outcome of mesothelioma. Nevertheless, this effect seems limited, and more effective approaches need to be developed.
    Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 06/2011; 6(9):1578-86. · 4.55 Impact Factor