Immune evader cancer stem cells direct the perspective approaches to cancer immunotherapy

Abstract

Exploration of tumor immunity leads to the development of immune checkpoint inhibitors and cell-based immunotherapies which improve the clinical outcomes in several tumor types. However, the poor clinical efficacy of these treatments observed for other tumors could be attributed to the inherent complex tumor microenvironment (TME), cellular heterogeneity, and stemness driven by cancer stem cells (CSCs). CSC-specific characteristics provide the bulk tumor surveillance and resistance to entire eradication upon conventional therapies. CSCs-immune cells crosstalk creates an immunosuppressive TME that reshapes the stemness in tumor cells, resulting in tumor formation and progression. Thus, identifying the immunological features of CSCs could introduce the therapeutic targets with powerful antitumor responses. In this review, we summarized the role of immune cells providing CSCs to evade tumor immunity, and then discussed the intrinsic mechanisms represented by CSCs to promote tumors' resistance to immunotherapies. Then, we outlined potent immunotherapeutic interventions followed by a perspective outlook on the use of nanomedicine-based drug delivery systems for controlled modulation of the immune system.

Keywords: CAR NK cells; CAR T cell; Cancer stem cells; Immune evasion; Nano-immunotherapy; Tumor microenvironment.

Fig. 1

Interaction between immune cells and CSCs in the immunosuppressive tumor microenvironment. a CSCs impair recruiting and maturation of DCs in tumor sites or use TGF-β signaling to induce DC differentiation into DCregs. b CSCs-derived TGF-β/CCLs induce the differentiation of M1 macrophage to M2 phenotype ones vs. M2 macrophages induce EMT and stemness in CSCs. c CSCs-derived TGF-β recruits MDSCs in tumor sites and reciprocally, MDSCs support CSCs stemness and propagation. d CSCs-derived TGF-β also recruits Tregs in tumor sites and reciprocally, Tregs-derived VEGF induces angiogenesis supporting CSCs survival and EMT. e PD-L1 + CSCs suppress T cells activation or induce their differentiation into Tregs-supporting tumors. f CSCs-derived IL-6 and TGF-β downregulate NK-activating receptors, and also, CSCs suppress NK cells activation through re-expression of MHC-II or shedding of MIC A/B and CD155-suppressing activating receptors

Fig. 2

Immunotherapies targeting CSCs. a Administrated NK cells or CAR NK cells target TAAs on CSCs and induce cytolysis and apoptosis via perforin/granzymes and TRAIL/FASL, respectively. Moreover, therapeutic antibodies target CD16 and TAA to mediate the ADCC process. b Ex vivo maturation of DCs exposed to CSCs-lysate/TAAs/peptides produce a vaccine that after administration arm the cytotoxic T cells in an MHC-1-TCR-dependent manner for targeting specific CSCs. c Administrated T cells or CAR T cells induce cytolysis and apoptosis in CSCs. Antibodies targeting immune checkpoint molecules such as PD1/PDL1, CD276, and CTLA4 could improve the anticancer immune responses. Anti-CD47 antibody sensitizes CSCs to cell-mediated phagocytosis. ADCC, antibody-dependent cellular cytotoxicity; FASL, FAS ligand; iDC, immature DC, mDC, mature DC; TRAIL, TNF-related apoptosis-inducing ligand

Fig. 3

Prospective nano-immunotherapy approaches to target CSCs. a The nucleic acids-based vaccine (mRNA or DNA) and CSCs-specific neoantigens are formulated into the nanoparticle displaying a DCs-targeting ligand to engage DCs followed by activation of CD4/8T cells in vivo. b Plasmid-encoding CAR against various CSC proteins can be loaded in CD3 targeted polymeric nanoparticles that genetically reprogramme T cells ex vivo or in vivo and thus T cells can be armed specificity to CSCs antigen of choice. c Owing to improving the pharmacokinetics of the immunomodulators and lowering their systemic exposure, the multiples of anti-PD1 and anti-CTLA4 antibodies can be bioconjugated to the surface of PEGylated liposomes to target T cells in vivo and promote their antitumor immune responses. d naAPC can generate coupling of co-stimulatory anti-CD28 antibody and MHC-1-Ig dimer on the surface of magnetic nanoparticles which induce TCR clustering and expand and activate the tumor-infiltrated T cells efficiently in vivo. Ag, antigen; ILipo, immunoliposomes; PEG, polyethylene glycol; naAPC, nano artificial antigen-presenting cell