Immunoregulatory/immune escape mechanisms associated with CSCs

Resistance of cancer cells to CTL-mediated immunotherapyResistance to targeted anti-cancer therapeutics. Benjamin Bonavida, Salem Chouaib (Eds). Springer International Publishing Switzerland (2015)

CSCs not only represent poor target cells for anti-tumor immune responses but they also display immune-regulatory properties. This indication originates from a variety of reports showing that these cells can secrete cytokines and soluble suppressive factors, such as Galectin-3, TGFβ, IL-10, IL-13, PGE2, PD-1, B7-H1, B7-H3, B7-H4, and GDF-15 [122, 157–161] (Table 1.2 and Fig. 1.2). The immunosuppressive activity of cancer initiating cells has been recently described both in GBM and melanoma, showing that CSC-like cells can inhibit T cell activation and proliferation by the induction of Tregs [122, 158, 159]. Furthermore, B7-H1, B7-H4, PD-1 and PD-L1 can be detected on CSCs from both GBM and CRC; these molecules inhibit T cell activation and proliferation following their encountering with CSCs, with implication for cell-mediated immunesurveillance of tumors (Table 1.2 and Fig. 1.2) [121, 123].

Table 1.2. Immunomodulatory molecules associated with CSCs

Resistance of Cancer Cells to CTL-Mediated Immunotherapy-Springer International Publishing (2015) T 1.2

Of note, the expression of B7 family members in brain tumor cells, including CSCs, has been related with their immunoresistance to T cell-mediated responses [157, 162]. CRC-CSCs express and secrete IL-4, with higher levels as compared with the autologous non-CSC tumor counterpart, which function is determinant for drug and apoptosis resistance and for the immune evasion of these cells [123, 163]. The membrane-associated IL-4 on CSCs predominantly exerts, by cell-to-cell contact, inhibition of T cell proliferation and of their anti-tumor activity (Table 1.2 and Fig. 1.2) [123]. Furthermore, the neutralization of this cytokine, by specific monoclonal antibodies, can restore T cell proliferation and anti-tumor activity [123]. In this model, soluble IL-4, though released by CRC-CSCs, leads only to partial in vitro inhibition of T cell reactivity [123]. Therefore, the blocking of IL-4 on CSCs can overcome at least one of the negative immunomodulatory activities of these cells and can rescue the activation and proliferation of both T and NK cells [123, 149]. These observations are in line with the demonstration that IL-4 signaling is a relevant key regulator for epithelial tumor behavior and lack of responsiveness to standard therapies [163, 164].

Moreover, CD200, a molecule that can block myeloid cell activities has been shown to be expressed by CSCs [165] while GBM-CSCs can evade from T cell recognition by the STAT3 pathway (Table 1.2 and Fig. 1.2) [158].

Despite the common feature of the immunosuppressive activity associated with CSCs, a variety of negative immunoregulatory signaling can be detected on these cells. Nevertheless, it appears clearly that these negative immune regulatory signals are not CSC-specific, but are shared with normal stem cells [166, 167]. Along this line, PGE2, acting by inhibiting macrophage and T cell activation, and indoleamine 2,3-dioxigenase (IDO) (Fig. 1.2), that depletes tryptophan preventing T cell activation and proliferation, are produced by CSCs to prevent immune reactivity and autoimmune diseases. Recently, the expression IDO has been found, following IFN-? treatment, on CSCs from GBM and CRC and has been found as responsible for the inhibition of T cell proliferation following their coculture in vitro with autologous CSCs (see Table 1.2 and Maccalli et al., personal communication).

Taken together, the observations reported, thus far, indicate that CSCs indeed display a low immunogenic profile and immunomodulatory functions that are typical features of “stemness” functions. Thus, immune-escaped CSCs, with low immunological properties, can favour the propagation and accumulation of cancer cells and can evade immunosurveillance. These cells may represent the self-renewal reservoir of a tumor, allowing cancer cell survival and progression.

The immunological characterization of CSCs still needs to be fully elucidated, however, the available information can contribute in identifying novel strategies that can revert the immunomodulatory activity of these cells and can target CSCs, such as the usage of immune checkpoint blockade agents [35] in combination with vaccine-based immunotherapy.

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