Ovarian cancer progression is controlled by phenotypic changes in dendritic cells
Open Access
- 20 February 2012
- journal article
- Published by Rockefeller University Press in The Journal of Experimental Medicine
- Vol. 209 (3), 495-506
- https://doi.org/10.1084/jem.20111413
Abstract
We characterized the initiation and evolution of the immune response against a new inducible p53-dependent model of aggressive ovarian carcinoma that recapitulates the leukocyte infiltrates and cytokine milieu of advanced human tumors. Unlike other models that initiate tumors before the development of a mature immune system, we detect measurable anti-tumor immunity from very early stages, which is driven by infiltrating dendritic cells (DCs) and prevents steady tumor growth for prolonged periods. Coinciding with a phenotypic switch in expanding DC infiltrates, tumors aggressively progress to terminal disease in a comparatively short time. Notably, tumor cells remain immunogenic at advanced stages, but anti-tumor T cells become less responsive, whereas their enduring activity is abrogated by different microenvironmental immunosuppressive DCs. Correspondingly, depleting DCs early in the disease course accelerates tumor expansion, but DC depletion at advanced stages significantly delays aggressive malignant progression. Our results indicate that phenotypically divergent DCs drive both immunosurveillance and accelerated malignant growth. We provide experimental support for the cancer immunoediting hypothesis, but we also show that aggressive cancer progression after a comparatively long latency period is primarily driven by the mobilization of immunosuppressive microenvironmental leukocytes, rather than loss of tumor immunogenicity.Keywords
This publication has 27 references indexed in Scilit:
- Molecular pathogenesis and extraovarian origin of epithelial ovarian cancer—Shifting the paradigmHuman Pathology, 2011
- Integrated genomic analyses of ovarian carcinomaNature, 2011
- Expression signatures of TP53 mutations in serous ovarian cancersBMC Cancer, 2010
- A Role for BRCA1 in Uterine LeiomyosarcomaCancer Research, 2009
- In situStimulation of CD40 and Toll-like Receptor 3 Transforms Ovarian Cancer–Infiltrating Dendritic Cells from Immunosuppressive to Immunostimulatory CellsCancer Research, 2009
- Depletion of Dendritic Cells Delays Ovarian Cancer Progression by Boosting Antitumor ImmunityCancer Research, 2008
- PILAR is a novel modulator of human T-cell expansionBlood, 2008
- Altered recognition of antigen is a mechanism of CD8+ T cell tolerance in cancerNature Medicine, 2007
- Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+T lymphocytes are prognostic factors of human ovarian cancerProceedings of the National Academy of Sciences of the United States of America, 2007
- Cancer immunoediting: from immunosurveillance to tumor escapeNature Immunology, 2002