Immune evasion by cancer stem cells

Abstract

Tumor immunity represents a new avenue for cancer therapy. Immune checkpoint inhibitors have successfully improved outcomes in several tumor types. In addition, currently, immune cell-based therapy is also attracting significant attention. However, the clinical efficacy of these treatments requires further improvement. The mechanisms through which cancer cells escape the immune response must be identified and clarified. Cancer stem cells (CSCs) play a central role in multiple aspects of malignant tumors. CSCs can initiate tumors in partially immunocompromised mice, whereas non-CSCs fail to form tumors, suggesting that tumor initiation is a definitive function of CSCs. However, the fact that non-CSCs also initiate tumors in more highly immunocompromised mice suggests that the immune evasion property may be a more fundamental feature of CSCs rather than a tumor-initiating property. In this review, we summarize studies that have elucidated how CSCs evade tumor immunity and create an immunosuppressive milieu with a focus on CSC-specific characteristics and functions. These profound mechanisms provide important clues for the development of novel tumor immunotherapies.

Keywords: ADCC, antibody-dependent cell mediated cytotoxicity; ALDH, alcohol dehydrogenase; AML, acute myeloid leukemia; ARID3B, AT-rich interaction domain-containing protein 3B; CCR7, C–C motif chemokine receptor 7; CIK, cytokine-induced killer cell; CMV, cytomegalovirus; CSC, cancer stem cell; CTL, cytotoxic T lymphocytes; CTLA-4, cytotoxic T-cell-associated antigen-4; Cancer stem cells; DC, dendritic cell; DNMT, DNA methyltransferase; EMT, epithelial–mesenchymal transition; ETO, fat mass and obesity associated protein; EV, extracellular vesicle; HNSCC, head and neck squamous cell carcinoma; Immune checkpoints; Immune evasion; KDM4, lysine-specific demethylase 4C; KIR, killer immunoglobulin-like receptor; LAG3, lymphocyte activation gene 3; LILR, leukocyte immunoglobulin-like receptor; LMP, low molecular weight protein; LOX, lysyl oxidase; MDSC, myeloid-derived suppressor cell; MHC, major histocompatibility complex; MIC, MHC class I polypeptide-related sequence; NGF, nerve growth factor; NK cells; NK, natural killer; NOD, nonobese diabetic; NSG, NOD/SCID IL-2 receptor gamma chain null; OCT4, octamer-binding transcription factor 4; PD-1, programmed death receptor-1; PD-L1/2, ligands 1/2; PI9, protease inhibitor 9; PSME3, proteasome activator subunit 3; SCID, severe combined immunodeficient; SOX2, sex determining region Y-box 2; T cells; TAM, tumor-associated macrophage; TAP, transporter associated with antigen processing; TCR, T cell receptor; Treg, regulatory T cell; ULBP, UL16 binding protein; uPAR, urokinase-type plasminogen activator receptor.