Cancer Stem Cells and Their Role in Tumor Dormancy and Immunosurveillance

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Background

Cancer stem cells or cancer initiating cells (CSCs/CICs) are present at relatively low frequency within tumor lesions and are endowed with self-renewal, multipotency and tumorigenic features. These rare cells have been involved in tumor formation, progression and metastatization and resistance to therapies. The tumorigenic properties of cancer stem cells have been demonstrated by xenotransplantation in immunodeficient mice. Transplantation of cells with “stemness” features leads to the neoformation of malignant lesions phenocopying the original tumor. These models suggest that tumors have a hierarchical organization. Following serial transplantation, phenotypically different subpopulations, including CSCs/CICs can be identified. In addition, the biological characterization of CSCs/CICs has provided evidence of their high degree of heterogeneity and plasticity. These properties are influenced by the interaction between CSCs/CICs and the tumor microenvironment (TME), where the CSC-associated niche, required for their survival and maintenance, is localized. The identification of “bona fide” CSCs has been shown to correlate with tumor prognosis and, a CSCs/CICs enrichment has been observed after development of resistance to therapies. However, the lack of standardized assays and tools to isolate CSCs/CICs and their high grade of plasticity has precluded definitive conclusions regarding the fate of these cells and their impact on tumor outcomes.

Immunotherapy represents a breakthrough therapeutic intervention, thanks to the clinical development and implementation of immune checkpoint blockade and adoptive cell therapy. This has resulted in improvement of patients’ overall survival in multiple cancer types. However, a significant proportion of patients are unresponsive or develop resistance to this type of therapy. Recent evidences suggest that CSCs/CICs display immunomodulating properties, including aberrant detection of HLA class I molecules and antigen processing machinery components and expression of immune checkpoints or immune regulatory molecules (e.g., PD-L1, B7-H3, Galectin-3, IDO, PGE2, etc.) leading to low susceptibility to cell-mediated immune responses. These findings indicate that, on the one hand, these cells can be responsible for immunological dormancy and remain quiescent until their crosstalk with the TME drives their entrance into cell cycling, ultimately leading to tumor recurrence or metastasis. On the other hand, CSCs/CICs can represent the tumor components responsible for resistance to immunotherapy.

The aim of this Research Topic is to provide a comprehensive overview of current and novel strategies targeting CSCs/CICs for studying tumor dormancy and immunosurveillance. We welcome the submission of Original Research, Review, Opinion and Perspective articles covering the following sub-topics:

1) Possible limitations of immune-based strategies in targeting CSCs/CICs and implications on efficacy.
2) Immunological profiling of CSCs /CICs and their crosstalk with the TME and host’s immune system, mechanisms orchestrating tumor immune evasion and immunological dormancy.
3) Immune-based therapies and their combinations, including the association with conventional treatment modalities, to overcome the limited efficacy of the available therapeutic options in targeting CSCs/CICs and leading to the complete eradication of tumors.
4) Available tools and experimental strategies to isolate CSCs/CICs from both solid and hematological tumors. Heterogeneity in the expression of markers, cellular plasticity in relationship with TME and lack of standardization among different experimental methods for their isolation and functional characterization.
5) Usage of mouse models to characterize the ‘stemness’ and tumorigenic functions of CSCs/CICs and to assess the hierarchical nature of tumor cell subpopulations.
6) Role of epithelial-to-mesenchymal transition (EMT), that can be influenced by inflammation and immune responses, in the generation of CSCs/CICs. These evidences establish a link between CSCs/CICs and tumor dormancy and open up new investigations on how cancer cells are capable of switching from dormancy to malignancy.

Keywords: cancer stem cells, cancer initiating cells, tumor dormancy, immune responses, tumor microenvironment

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