The role of immune checkpoints in modulating cancer stem cells anti-tumor immune responses: implications and perspectives in cancer therapy

Cancer stem cells (CSCs) are a minor subpopulation of tumor cells characterized by self-renewal capacity and stemness features and are responsible for tumor progression and therapy resistance. Several studies have shown that CSCs possess immunomodulatory properties that allow them to evade from immune responses. One of the mechanisms by which CSCs can escape from immune cells recognition and killing is represented by the overexpression of immune checkpoints (ICPs). The observation that cancer patients may still display or acquire resistance to immunotherapy despite targeting the PD-1/PD-L1 axis, highlights the importance of other ICPs as potential mediators of immune resistance. In this review, we summarize the immunomodulatory properties of CSCs and comprehensively discuss the crosstalk between these cells and selected ICPs (i.e., B7-H3, B7-H4, CD200 and CD155, VISTA, TIGIT, CD47, CD70, CEACAMs, and galectins) that are thought to be involved in CSC mediated immune evasion. Open questions regarding the immunological profile of CSCs, especially in relation to ICPs expression and their underlying regulatory mechanisms, are also addressed. Improved immunological profiling of CSCs will contribute to the identification of prognostic and predictive biomarkers for cancer patients and the development of effective therapeutic interventions that may lead to the eradication of malignant tumors.