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Lung cancer recruitment of CD14+ cells results in an immunosuppressive phenotype and improved tumor survival under stress conditions
© Schenk and Dietz 2015
Published: 4 November 2015
We have previously shown that a higher burden of CD14+HLA-DRlo/neg cells in the peripheral blood of cancer patients is associated with systemic immune suppression and a poor outcome. We have also reported that CD14+ cells isolated from healthy donors are converted to the immunosuppressive CD14+HLA-DRlo/neg phenotype when cocultured with tumor cell lines or primary tumor cultures. Therefore, one potential mechanism of CD14+HLA-DRlo/neg generation in cancer patients is the recruitment of CD14+ cells to the tumor microenvironment. In this study, we tested the ability of multiple human lung cancer cell lines to recruit CD14+ cells, convert normal donor CD14+ cells to CD14+HLA-DRlo/neg, and the impact on tumor survival under stress conditions in the presence of CD14+HLA-DRlo/neg cells. Monocyte recruitment by cell line supernatants was studied using freshly isolated CD14+ cells and measured in real time with live cell imaging. Monocytes from 10/10 unique healthy donors migrated towards H23 supernatant in a dose dependent fashion. Supernatants from other human lung cancer cell lines including H889, H1155, H1581, and H1975 also recruited healthy donor monocytes 6 to 9 fold greater than culture media alone. The CD14+ phenotype resulting from interaction with lung cancer cell lines was studied in a 2 day coculture system. Coculture of H1581 with monocytes from 27 of 29 unique healthy donors resulted in a downregulation of monocyte cell surface expression of HLA-DR by 48.7% ± 22.1%, a phenotype known to mediate both local and systemic immune suppression. C14+ HLA-DR downregulation after coculture was observed with H23 (17/18 unique healthy donors, 49.7% ± 22.1% HLA-DR reduction) and H889 (5/6 unique healthy donors, 47.3% ± 16.1% HLA-DR reduction). Importantly, CD14+ cells promoted lung tumor cell line survival under stress conditions. After 6 days of low serum growth conditions, the survival and proliferation of H23 and H1581 was approximately 2 fold greater when cocultured with CD14+ cells than without monocytes. H889 continuously exposed to cisplatin in culture had significantly improved survival when co-cultured with monocytes for 2 days prior to cisplatin exposure. In conclusion, we have demonstrated multiple lung cancer cell lines recruit and transformation monocytes to the HLA-DRlo/neg phenotype. These data suggest monocyte cancer cross-talk results in improved tumor survival when exposed to the likely in vivo conditions of a nutrient poor environment or chemotherapy independent of local immune suppression and angiogenesis.
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.