Cancer stem cells in immunoregulation and bypassing anti-checkpoint therapy.

Tumor microenvironment (TME) takes critical roles in tumor resistance to immune checkpoint inhibitors (ICIs) including anti-programmed death-1 (PD-1) or anti-programmed death-ligand 1 (PD-L1). Cancer stem cells (CSCs) are one of the key components of TME that play important roles in immunoregulation and therapy resistance. CSCs suppress CD8 T cell infiltration, and promote recruitment of type 2 macrophages (M2) and the activity of type 2 neutrophils (N2). There is a positive association between CSC expansion with high PD-L1 expression in TME, and the expression of PD-L1 is higher in CSCs than cancer cells. PD-L1 expression in metastatic cancer cells induces a dedifferentiation program through stimulating an epithelial-mesenchymal transition (EMT) profile, thereby replenishing CSC proportion inside tumor. Conversion from EMT to mesenchymal-epithelial transition (MET) downregulates PD-L1 expression on CSCs and non-CSCs and increases ICI efficacy. There is an evidence of CSC replenishment secondary to the anti-PD-1 therapy. Targeting CSCs is, in fact, a key step in effective tumor breakdown and reducing tumor recurrence after immunotherapy. A number of signaling are involved in CSC enrichment within tumor area, among them a key focus is over transforming growth factor-β (TGF-β). TGF-β induces a dedifferentiation program, and its activity as a bridge between EMT with increased PD-L1 level rationalizes application of dual TGF-β/anti-PD-L1 inhibitors as an effective strategy for reinvigorating immunoactivities in patients under ICI therapy. In this review, we aimed to discuss about connections between CSCs with immune ecosystem of tumor and the impact of such interactions on cancer responses to ICI therapy.