The receptor protein Dectin-1 recognizes structures found on cancerous cells, and then triggers an anti-tumor immune response.
The immune system is best known for its role in defending the body against microbial infections. People carrying mutations that affect the immune system are, therefore, highly susceptible to infectious diseases and usually require continuous care to avoid infections. However, it has also been proposed that the immune system can eliminate cancer cells. This idea, known as immune surveillance, is several decades old, but there is little experimental evidence to support it. In large part, this is because the mechanisms used by the body to recognize cancer cells remain poorly understood.
A key feature of the immune system is its ability to distinguish between pathogens (‘non-self’) and the body's own cells (‘self’). Immune cells detect certain components that are found in many microorganisms, such as the complex carbohydrates that make up bacterial and fungal cell walls. Because these components are unique to microbes, detecting them allows the innate immune response—the body's first line of defence—to identify the cell they came from as ‘non-self’ and potentially harmful, and then act to neutralize the threat.
The carbohydrates are recognized by the so-called pattern-recognition receptors, such as Toll-like receptors and C-type lectin receptors, which are found in two types of immune cell—dendritic cells and macrophages (Takeuchi and Akira, 2010). Pathogens cannot easily evade detection because the components that are recognized by the receptors are essential for microbial fitness and survival.
This approach cannot be used to detect tumors because they develop from the host's own cells. Rather, in order to perform immune surveillance the immune system has to be able to distinguish tumor cells from normal cells. One way that this would be possible is if cancer cells produce signals that can be detected by the immune system. Clearly, if such signals exist, they would be the first feature to be lost by the cancer cells as they evolve under the selection pressure imposed by immune surveillance. Unless, that is, getting rid of these signals comes with a significant cost to the cancer cell.
Now, in eLife, Tadatsugu Taniguchi of the University of Tokyo and co-workers—including Shiho Chiba, Hiroaki Ikushima and Hiroshi Ueki as joint first authors—report evidence that immune surveillance does indeed rely on this strategy. They report that the pattern-recognition receptor Dectin-1 plays a crucial role in recognizing a process called tumor cell-associated glycosylation and in initiating an anti-tumor innate immune response (Chiba et al., 2014).
Glycosylation is a reaction where a carbohydrate molecule called a glycan is added to a protein. Altered glycosylation is a universal feature of tumor cells (Varki et al., 2009). By increasing where and how much glycosylation occurs on their surface, many tumor cells develop an advantage over other cells when migrating to and spreading through other organs.
Chiba et al. found that two proteins play crucial roles in suppressing the spread of cancer: Dectin-1 and IRF5 (Figure 1). Dectin-1 recognizes molecules called β-glucans that are found on fungal cell walls (Brown, 2006). When Dectin-1 recognizes its target, the transcription factor IRF5 activates innate immunity in response (del Fresno et al., 2013). Chiba et al. now show that Dectin-1 also recognizes particular glycosylation associated structures called N-glycan structures, which are highly expressed in several tumor cell lines—but not in non-cancerous cells. When N-glycan structures are detected, Dectin-1 triggers an anti-tumor immune response.
Natural killer (NK) cells are lymphocytes (or white blood cells) that can kill cancer cells and so could play an important role in immune surveillance (Vivier et al., 2012). Chiba et al. found in their experimental model that natural killer cells are indeed required for the elimination of tumor cells. Furthermore, natural killer cells rely on Dectin-1 expressed on dendritic cells and macrophages in order to kill tumor cells; the findings therefore reveal a new functional link between dendritic cells, macrophages and natural killer cells.
Chiba et al. have taken an important step towards understanding how the anti-tumor immune response works. As is normal for a brand-new finding, this work raises a number of important questions. The level and/or the specific structural patterns of glycosylation on tumor cells appears to be important for the fitness of cancer cells. Therefore, an immune surveillance system based on cell surface glycan recognition may have evolved to prevent cancer cells themselves evolving in a way that enables them to evade the anti-tumor immune response. In this regard, it would be important to know whether Dectin-1 is activated by either an altered structure or increased level of N-glycans on tumor cells.
It is possible that the total level or specific structural variants of cell surface N-glycans may reflect the metabolic state of the cell. For example, the hexosamine biosynthetic pathway—which is used by cells to produce a particular type of sugar—is more active than normal in some cancers and can affect the glycosylation patterns of cell surface proteins (Wellen et al., 2010). It would be very interesting to investigate whether Dectin-1 (and other C-type lectins) evolved to detect the increased activity of the hexosamine biosynthetic pathway through its effect on cell surface N-glycans, as a proxy for cancer cells (Figure 1).
Dectin-1: a signalling non-TLR pattern-recognition receptorNature Reviews Immunology 6:33–43.https://doi.org/10.1038/nri1745
Essentials of GlycobiologyEssentials of Glycobiology, New York, Cold Spring Harbor.
Targeting natural killer cells and natural killer T cells in cancerNature Reviews Immunology 12:239–252.https://doi.org/10.1038/nri3174
Downloads (link to download the article as PDF)
Download citations (links to download the citations from this article in formats compatible with various reference manager tools)
Open citations (links to open the citations from this article in various online reference manager services)
Cancer-associated fibroblasts (CAFs) are a heterogeneous population of mesenchymal cells supporting tumor progression, whose origin remains to be fully elucidated. Osterix (Osx) is a marker of osteogenic differentiation, expressed in skeletal progenitor stem cells and bone-forming osteoblasts. We report Osx expression in CAFs and by using Osx-cre;TdTomato reporter mice we confirm the presence and pro-tumorigenic function of TdTOSX+ cells in extra-skeletal tumors. Surprisingly, only a minority of TdTOSX+ cells expresses fibroblast and osteogenic markers. The majority of TdTOSX+ cells express the hematopoietic marker CD45, have a genetic and phenotypic profile resembling that of tumor infiltrating myeloid and lymphoid populations, but with higher expression of lymphocytic immune suppressive genes. We find Osx transcript and Osx protein expression early during hematopoiesis, in subsets of hematopoietic stem cells and multipotent progenitor populations. Our results indicate that Osx marks distinct tumor promoting CD45- and CD45+ populations and challenge the dogma that Osx is expressed exclusively in cells of mesenchymal origin.
There is strong evidence that the pro-inflammatory microenvironment during post-partum mammary involution promotes parity-associated breast cancer. Estrogen exposure during mammary involution drives tumor growth through neutrophils’ activity. However, how estrogen and neutrophils influence mammary involution are unknown. Combined analysis of transcriptomic, protein, and immunohistochemical data in BALB/c mice showed that estrogen promotes involution by exacerbating inflammation, cell death and adipocytes repopulation. Remarkably, 88% of estrogen-regulated genes in mammary tissue were mediated through neutrophils, which were recruited through estrogen-induced CXCR2 signalling in an autocrine fashion. While neutrophils mediate estrogen-induced inflammation and adipocytes repopulation, estrogen-induced mammary cell death was via lysosome-mediated programmed cell death through upregulation of cathepsin B, Tnf and Bid in a neutrophil-independent manner. Notably, these multifaceted effects of estrogen are mostly mediated by ERα and unique to the phase of mammary involution. These findings are important for the development of intervention strategies for parity-associated breast cancer.