Figure 4.

Proposed role of CSCs in tumor immune escape. Elimination (Left): malignant transformation requires oncogenic mutations (flash) to accumulate within an individual cell. If such mutations occur in a differentiated cell, this cell will upregulate activatory NK cell receptor ligands and present tumor-specific peptides via MHC class Ia molecules (both orange). Thus, these cells can be detected and eliminated by the immune system, leading to restoration of normal tissue. Equilibrium (Center): stem cells (SC) are long-lived and express a multitude of immunosuppressive factors (dark purple). Hence, they may accumulate oncogenic mutations without being cleared by the immune system. However, CSCs are initially confined to stem cell niches (green) and limited to asymmetric divisions. More differentiated daughter cells inherit all malignant mutations, but are more immunogenic and could thus be eliminated by the adaptive immune system. Thus, a robust equilibrium may emerge. Escape (Right): mechanisms contributing to tumor immune escape include defects in tumor immunosurveillance, immunoediting, or the expansion of CSCs. The immune system may lose its ability to constrain tumors due to aging, immunosuppressive therapies, diseases or other factors. Immunoediting describes the evolutionary adaptation of individual tumor subclones to the selection pressure exerted by the immune system. It will ultimately lead to expansion of less-immunogenic or more immunosuppressive subclones. Non-immunogenic CSCs may further acquire the ability to expand independently of their niches, which may lead to the outgrowth of poorly differentiated tumors.