Immunological profile of CSCs

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

The characterization of the immune profile of CSCs is complementary to their genomic/molecular assessment, and is mandatory to determine their susceptibility to innate and/or adaptive immune responses. Along this line, it is worthy to assess the expression of Tumor Associated Antigens (TAAs) and of the efficiency of their antigen processing and presentation by CSCs, as well as their expression profile of regulatory molecules of immune responses. Several groups have carried out studies in this field, however, thus far, this issue has not been clearly dissected.

The characterization of the immune profile of CSCs, including the expression of Major Histocompatibility Complex (MHC) class I and class II, of Antigen-Processing Machinery (APM) and of other immunologically relevant molecules has been determined in CSCs deriving from tumors with different histological origins, such GBM, melanoma and colorectal cancer (CRC) [121–124].

Low or negative expression of MHC class I and class II molecules is detected in these CSCs as compared with the autologous non-CSC counterpart of tumors [124, 125]. Moreover, low susceptibility of CSCs to IFN (α or γ) or de-methylating agent (5-Aza-2′-deoxycytidine), with some heterogeneity depending on the tissue origins, to increase the expression of MHC and APM molecules and of ligands of the receptor NKG2D (NKG2DLs) has been reported [124, 125]. Similar results are observed by Wu et al. [126], showing failure by GBM CSCs to express sufficient levels of MHC class I molecules and NK cell activatory ligands, leading to lack of susceptibility to NK-mediated lysis [126]. Along this line, melanoma-derived CSCs but not their autologous non-CSC counterparts have been found to be defective for MHC class I and class II molecules [122]. Taken together these evidences indicate that low efficiency in antigen processing and presentation of TAAs can occur in CSCs, revealing that these cells represent poor targets for cell-mediated immune responses (Fig. 1.2).

These observations are in line with the documentation that molecular defects can occur in MHC and APM molecules in bulk tumors with different tissue origins [127–130].

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

Fig. 1.2. The immunomodulatory activity of CSCs is regulated by the interaction of multiple stimulatory and inhibitory molecules. The expression or not of immune-related molecules, such as MHC molecules, NKG2DLs and other ligands of NK activatory receptors, can result in inducing or not efficient T cell-mediated responses against CSCs. On the other hand, negative immunomodulatory molecules such as PD-L1, CD200, IDO and IL-4 can suppress cell-mediated immunosurveillance. Soluble factors (TGFβ, hepatocyte GF, IL-4, IL-6, IL-10, IL-13 and prostaglandin E2) released by CSCs can inhibit effector functions and lead to the differentiation of immune cells with regulatory activity, T regulatory cells (Tregs) and myeloid-derived suppressor cells (MDSCs) or of Th2-type T cell responses

This immune profile of CSCs resembles that of the physiological normal stem cells. In fact, embryonic stem cells (ESCs) express low levels of classical antigenpresenting MHC class, no MHC class I and II molecules. Moreover, they express low levels or are negative for the ligands of activatory NK cell receptor (NKp44, NKp30, NKp46, and CD16) [131]. Similarly, normal heamatopoietic stem cells display down-regulation of MHC class I molecules [132] thus, suggesting that low MHC molecules expression is a common feature of “stemness” allowing their preservation and leading to the escape from cell-mediated immune responses. Nonclassical MHC molecules, that can exert inhibitory signals (e.g. HLA-G), are commonly expressed at high levels by both ESCs and mesenchymal stem cells (MSCs) contributing to the evasion from recognition by T or NK cells [133–136].

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