The expression of HLA class I and class II molecules and APM has been investigated in CSCs/CICs isolated from colorectal cancer (CRC) and glioblastoma multiforme (GBM) showing an overall aberrant expression of these molecules, with, in some cases, failure in their modulation by the pre-treatment with IFNs (both alpha and gamma) or DNA demethylating agent (5-Aza CdR) [
64,
65]. This impairment in antigen processing and presentation by CSCs/CICs lead, upon co-culture of these cells with autologous T cells, to a preferential selection and differentiation of TH2 type T cells and failure in eliciting effector functions [
64,
65]. The suboptimal expression of HLA class I molecules and APM components was also reported in CSCs/CICs isolated from different type of solid tumors [
64‐
69]. These peculiar observations suggested that the defective expression of HLA molecules could represent a tool for the identification of CSCs/CICs [
70]. On the contrary, the side population (SP) cells derived from CRC and endowed with stemness properties, showed detectable level of HLA class I molecules as well susceptibility to antigen-specific cytotoxic T lymphocytes (CTLs) [
71], however this study has been performed using long-term
in vitro established cell lines, that could have lost phenotypic properties of primary CSCs/CICs. Indeed, stem-like cells isolated by sphere-forming assay displayed aberrant expression of HLA class I and APM components [
16,
65]. Contradictory results were obtained also in glioblastoma multiforme (GBM); CSCs/CICs isolated as sphere forming cells from this tumor have been shown to exhibit the expression of HLA class I molecules [
72] while, when applying these analyses to primary GBM-derived sphere forming cells, defective expression of HLA class I and APM molecules was detected [
64]. Stem-like cells expressing ABCB5 and isolated from melanoma were found to express suboptimal levels of HLA class I molecules while they were positive for HLA class II (45). APM components (e.g., LMP2, LMP7 MECL-1, TAP1 and TAP2) detected through mRNA analyses were found to be expressed in tumor sphere-models from different solid malignancies, representing a tool for
in vitro enrichment of stem-like cells and for the investigation of micro-metastasis [
73]. However, HLA class I and class II molecules were down-modulated in these cells as compared to differentiated tumor cells, also following their pre-treatment
in vitro with IFN-γ, highlighting an impairment of antigen presentation by these cells [
64]. It needs to be considered that this study did not analyze the expression at protein levels of APM molecules, therefore post-transcriptional mechanism could affect their expression. Moreover, long term
in vitro established cell lines were used to isolate tumor cell spheres while in other studies reporting defective expression of APM components, primary CSCs/CICs have been investigated. These examples highlight that an overall suboptimal immunogenic potency by CSCs/CICs resulting in low or impaired susceptibility to T cell mediated immune responses (Fig.
1). This represents a mechanisms of evasion by immune responses that is shared with normal stem cells, that could represent a typical feature of cells with stemness properties [
74]. Importantly, the failure in the expression of HLA molecules by tumor cells was found as one of the mechanisms of failure of the clinical activity of immune checkpoint blockade agents in cancer patients [
75,
76], indicating that either CSCs/CICs can display immune evasion mechanisms shared by differentiated tumor cells or that indeed the suboptimal expression of HLA molecules of these cells and their resistance to T cell recognition can protect these cells from immunotherapy interventions, leading to tumor recurrence or progression. However, the lack of standardization in methods for both, the isolation of cells with stemness properties and to analyze HLA and APM molecules, represents a limitation in providing conclusive results. Nevertheless, detailed analysis to identify the molecular mechanisms that lead to aberrant expression of HLA molecules and APM components are warranted.
The suboptimal expression of HLA class I molecules if associated with detectable NKG2D ligands, can drive the increased susceptibility of CSCs/CICs to Natural Killer (NK) cells. This phenomenon has been observed in CSCs/CICs from glioma, melanoma, and CRC [
68,
77‐
79]. However, down-modulation of NKG2D ligands on CSCs/CICs has been documented, e.g., in GBM patients [
64] suggesting that the expression of low levels of NK cell activating ligands can result in the impairment of anti-CSCs/CICs innate immune responses (Fig.
1). The expression profile of molecules activating innate immune responses on CSCs/CICs can be affected by their crosstalk with TME, and thus, by their plasticity that can influence the fate
in vivo of these cells.