Cancer Stem Cell Antigens and the Tumor Microenvironment

As was discussed earlier for mature tumor cells, expression of certain tumor-associated antigens on cancer stem cells can profoundly influence their microenvironment. Evidence is beginning to accumulate that some of the tumor antigens described on mature tumor cells are also present on cancer stem (like) cells. One of these antigens is MUC1. Because a lot is known about its immunoregulatory and oncogenic functions in mature tumor cells, we will present a hypothetical picture of its impact on the microenvironment of a cancer stem cell.

A tissue specific adult stem cell that has accumulated a significant number of oncogenic mutations over its long life might eventually turn malignant if it successfully passes through the many survival checkpoints. In comparison to normal stem cells that reside in their niche and depend on interactions with the surrounding stromal cells that regulate survival and stem cell divisions, a transformed stem cell becomes independent from the niche. During this process we suspect that the malignant stem cell will start expressing modified tumor forms of some self-antigens. Overexpression of the tumor form of MUC1 could at that point serve to protect the cancer stem cell from apoptosis, increase its proliferation and perhaps signal differentiation into tumor progenitor cells. At the same time, it will send a chemotactic signal to the cells of the innate immune system to survey the emerging tumor site, but also provide a supportive cytokine milieu for further growth of the nascent tumor. The host immune system eventually becomes aware of the changes in the cancer stem cell niche in part through the recognition of the modified self-antigens. In the very early stage of tumor growth, the local microenvironment is not yet tumor supportive and it is not immunogenic either. The immune system recognizes the tumor-induced changes in the self-molecules but this recognition is still below the threshold of full activation. During the time when a few cancer stem and progenitor cells are tolerated by the immune system, they have the opportunity to shape their microenvironment to support their further growth. This includes promotion of an immunosuppressive environment that will inhibit antitumor immunity once it is formed and arrives to the tumor site. Expression of MUC1, for example, can influence and manipulate cell signaling via phosphorylation of its C-terminal domain and thus stimulate gene transcription and influence uncontrolled cell proliferation. Overexpression of phosphorylated MUC1 can compete with E-cadherin expressed by neighbouring cells, for binding to P-catenin and stimulating anchorage independent growth. The abundance of sialic acid moieties on tumor MUC1 can mediate repulsion from a united cell structure and eventually help migration of the tumor cells. This is furthermore facilitated by the extended rigid structure of MUC1. MUC1 has been reported to compromise complement-dependent cytotoxicity on mucin expressing tumor cells. When cells are coated with MUC1, complement is activated very far away from the cancer cell surface and thus, the membrane attack complex that forms pores in the cell membrane, can not be initiated or could not reach the cell membrane [173].

As stem cells convert to transient amplifying cells they become more and more independent from contact inhibitory growth and growth factors and turn more aggressive, eventually generating a heterogeneous mature tumor cell population that forms the tumor mass. Throughout this process, MUC1 expression is high and its glycosylation is low. This serves to attract immature DCs to the nascent tumor microenvironment. Immature DCs express various C-type lectin receptors that can bind and internalize MUC1. Immature DCs can also take up other tumor antigens through their active endocytosis. This would at first appear as a very beneficial process that could favor development of effective tumor immunosurveillance.

However, just the opposite may happen. In order to effectively present MUC1 and other tumor antigens to T cells, DCs need to fully mature into cells with high stimulatory capacity promoted by high levels of co-stimulatory molecules and cytokine production, preferably IL-12. This does not appear to happen after their interaction with tumor MUC1. Immature DCs attracted to the site on MUC1-expressing tumor cells mature into regulatory DCs that secrete high concentration of IL-10, but not IL-12, and express very low levels of co-stimulatory molecules [174, 175]. These DCs also produce proinflammatory cytokines IL-6 and TNF-alpha and promote generation of T cells that produce IL-13. IL-13 can have a dual function in the tumor microenvironment. On one hand it can suppress CTLs, and induces the generation of regulatory T cells, thus preventing effective immune surveillance of the tumor. On the other hand, it serves as a paracrine growth factor for tumor cells that express IL-13 receptor. Another important component of the tumor microenvironment is represented by the stromal fibroblasts, which become activated and begin to secrete TGF-0 and thus, further inhibit antitumor immunity. All of these events, in part driven by MUC1, are known to happen in the environment of a mature tumor. The likelihood is high that these processes also influence the cancer stem cell niche and are responsible for tumor development and/or recurrence.

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