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.

Cancer Stem Cells: Emerging Key Players in Immune Evasion of Cancers

“…Miao et al (2019) demonstrated that TGF-β-enriched CSCs dampened the cytotoxicity of adoptive T cells by promoting the exhaustion state through CD80-CTLA4 interaction in squamous cell carcinoma. The findings of adaptive immune resistance raised from CSCs against immunotherapy echoes with the previously proposed immunosuppressing feature of CSC, and furthermore emphases CSC as the root of tumor relapse (Tsuchiya and Shiota, 2021).…”

“…However, the preferential tumorigenic capability of CSCs in NOD/SCID mice suggests that there are underlying immunosuppressive mechanisms for CSCs to dodge from NK cell specific killing ( Al-Hajj et al, 2003 ; Tsuchiya and Shiota, 2021 ). It has been reported that CSCs escape NK-mediated cytotoxicity via various mechanisms by tuning NK receptors.…”

“…A substantial body of literature has extensively described the interactions of tumor bulks with the immune system; however, investigations have only begun to elucidate the relationship of CSCs and immune cells within the TME, paving the way for the development of rational therapeutic strategies to explore CSC-immune dynamics. The capability of CSCs in tumor initiation in partly immunocompromised mice e.g., SCID or NOD/SCID mice (T, B cells defect but NK cells present) suggests that these cells are empowered with the definitive ability to evade immune detection and surveillance, whereas non-CSCs require a higher extent of deficiency in immune system for generating tumors in NSG mice (lack of T, B, and NK cells) ( Tsuchiya and Shiota, 2021 ). Increasing evidence has demonstrated that there is a reciprocal interaction between CSCs and various immune cells.…”

Cancer Stem Cell for Tumor Therapy

“…The recent evidence shows that CSCs harbor the capacity of immuno-suppression via several mechanisms; it was revealed that some well-known immunosuppressive molecules, such as PD-L1 and CTLA-4, were higher expressed in CSCs than in common tumor cells [ 174 , 175 ]. Antigen presentation plays a crucial role in cells immunity, it was indicated that CSCs could impair the antigen presentation by downregulating the expression of MHC molecules and some antigen processing molecules, such as transporter associated with antigen processing (TAP) and β-macroglobulin [ 176 ]; researchers also found that the abnormal expression of tumor-associated antigens in CSCs contributed to immune invasion via reducing immunogenicity; CSCs could also promote to build suppressive TME via recruiting some immune cells, such as tumor-associated macrophage (TAM) and regulatory T cell(Treg), and secreting some immuno-suppressive molecules, such as CD200, TGF-βand IFNs, to inhibit CSCs-targeted immune-response [ 177 ], Hiroyuki Tsuchiya et al also summarized that CSCs could impair NK cell function, such as inhibiting the release of cytolytic granules, regulating the expression of the different NK-cell ligands, to escape immune response, they thought the characteristic of immune invasion was a more fundamental feature to CSCs than the tumor-initiating property [ 178 ]. It is necessary to find some new strategies to target CSCs via immunity methods.…”

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

“…However, the genetic and cellular heterogeneity of the surrounding tumor microenvironment (TME) complicated the clinical efficacy of those treatments, which requires further understanding of the multiple aspects of tumor biology [ 4 ]. Along with the genetic and epigenetic instabilities, the nongenetic intra-tumor heterogeneity and plasticity conduct therapy failure due to the presence of the rare population of cancerous cells known as cancer stem cells (CSCs) or cancer-initiating cells (CICs) [ 5 , 6 ].…”