Abstract
The ability of immune cells to sense changes associated with malignant transformation as early as possible is likely to be important for the successful outcome of cancer immunosurveillance. In this process, the immune system faces a trade-off between elimination of cells harboring premalignant or malignant changes, and autoimmune pathologies. We hypothesized that the immune system has therefore evolved a threshold for the stage of transformation from normal to fully malignant cells that first provides a threat (danger) signal requiring a response. We co-cultured human macrophages with a unique set of genetically related human cell lines that recapitulate successive stages in breast cancer development: MCF10A (immortalized, normal); MCFNeoT (benign hyperplasia); MCFT1 (atypical hyperplasia); MCFCA1 (invasive cancer). Using cytokines-based assays, we found that macrophages were inert towards MCF10A and MCFNeoT but were strongly activated by MCFT1 and MCFCA1 to produce inflammatory cytokines, placing the threshold for recognition between two premalignant stages, the earlier stage MCFNeoT and the more advanced MCFT1. The cytokine activation threshold paralleled the threshold for enhanced phagocytosis. Using proteomic and transcriptomic approaches, we identified surface molecules, some of which are well-known tumor-associated antigens, that were absent or expressed at low levels in MCF10A and MCFNeoT but turned on or over-expressed in MCFT1 and MCFCA1. Adding antibodies specific for two of these molecules, Annexin-A1 and CEACAM1, inhibited macrophage activation, supporting their role as cancer “danger signals” recognized by macrophages.
Highlights
Medical and evolutionary sciences have traditionally developed in relative isolation [1]
We incubated primary human monocyte derived macrophages for 24 hours with the MCF cell lines representing the various stages of malignant transformation, from normal (MCF10A) to premalignant (MCFNeoT and MCFT1) to invasive breast cancer (MCFCA1), and quantified 13 secreted cytokines using a cytometric bead array
We focused on i) cytokines with concentrations above the detection threshold, ii) cytokines secreted at different levels depending on the cancer cell line used in the co-incubation, iii) cytokines secreted in responses to more than one cell line, iv) cytokines for which concentrations were significantly different in co-culture compared to mono-culture
Summary
Medical and evolutionary sciences have traditionally developed in relative isolation [1]. In the 1970s, evolutionary and ecological concepts began to be applied to cancer initiation and progression [2, 3]. Since this seminal work, several studies explored the processes of somatic cellular selection and evolution leading to malignant transformation, metastasis or resistance to therapies [4,5,6]. Tumor cells vary in their ability to evade the immune system and the “invisible” clones present a selective advantage and proliferate at the expense of others [7]. Premalignant cells may be challenging for the immune system because they are mostly self with initially only a few characteristics of tumor cells [11]
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