Dr. Weeks’ Comment: More powerful clarity about the importance of targeting the cancer STEM cell with anti-inflammatory agents and immunotherapy. Powerful words follow:
The targeting of CSCs/CICs by immunotherapy could result in the complete tumor eradication and stable clinical responses in cancer patients. This goal could be achieved by the design of combination of strategies based on innate and/or antigen-specific T cell responses with immunoregulatory agents that can render CSCs/CICs susceptible to cell-mediated immunosurveillance. In cases where epigenetic factors are responsible for low antigen presentation, the usage of demethylating agents could represent a potential strategy to overcome the low expression of HLA molecules.
Cancer Microenviron 2019 Dec;12(2-3):133-148. doi: 10.1007/s12307-019-00233-1. READ ENTIRE ARTICLE HERE
The Cross Talk Between Cancer Stem Cells/Cancer Initiating Cells and Tumor Microenvironment: The Missing Piece of the Puzzle for the Efficient Targeting of These Cells With Immunotherapy
Shilpa Ravindran 1, Saad Rasool 1, Cristina Maccalli 2
Abstract
Cancer Stem Cells/Cancer Initiating Cells (CSCs/CICs) is a rare sub-population within a tumor that is responsible for tumor formation, progression and resistance to therapies. The interaction between CSCs/CICs and tumor microenvironment (TME) can sustain “stemness” properties and promote their survival and plasticity. This cross-talk is also pivotal in regulating and modulating CSC/CIC properties. This review will provide an overview of the mechanisms underlying the mutual interaction between CSCs/CICs and TME. Particular focus will be dedicated to the immunological profile of CSCs/CICs and its role in orchestrating cancer immunosurveillance. Moreover, the available immunotherapy strategies that can target CSCs/CICs and of their possible implementation will be discussed. Overall, the dissection of the mechanisms regulating the CSC/CIC-TME interaction is warranted to understand the plasticity and immunoregulatory properties of stem-like tumor cells and to achieve complete eradications of tumors through the optimization of immunotherapy…
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Natural killer (NK) cells are the first line of defense against cancer development and metastasis. NK cells have been described to efficiently recognize and kill in vitro CSCs/CICs isolated from CRC, melanoma and glioblastoma [68, 78, 93, 94]. The efficiency of NK cell-mediated lysis of CSCs/CICs was dependent on the expression of NCR ligands (NKp30 and NKp44), NKG2D ligands and when suboptimal or negative expression of HLA class I molecules were found on the surface of CSCs/CICs (Fig 1) [68, 78, 93–95]. Tallerico et al. found that CSC/CIC but not their differentiated counterpart of CRC is susceptible to NK cells [77]. Similar results have been reported in GBM and melanoma, highlighting that the amount of ligands of activatory NK receptors on CSCs/CICs was determinant for efficient innate immune responses [68, 77, 78]. In patients with acute myeloid leukemia (AML), the suboptimal expression of NKG2D ligands has been described as a mecahnisms of escape by tumor cells from NK cell recognition [96], confirming that these molecules can affect the susceptibility of cancer cells to innate responses. The observations that NKG2D ligands could represent as biomarkers for prediction of clinical responses to immune checkpoint blockade in melanoma highlight that the pattern of NKG2D ligands expression by tumor cells can affect the type and efficiency of elicited anti-tumor immune responses [97]. Therefore, the levels and pattern of expression of NKG2D ligands by tumor cells, including CSCs/CICs could be a predictive marker for the choice of the type of immunotherapy interventions.
Dendritic cells (DCs) are antigen presenting cells (APCs) that can activate either innate or adaptive immune responses [98]. In addition, they play an important role in the formation of anti-tumor T- and B cell immunologic memories [99]. Immature DCs can capture the tumor-derived antigens by phagocytosis or pinocytosis and then migrate to lymphoid organs where they present these TAAs in the form of HLA/peptide complexes to T cells, resulting in antigen-specific immune responses [100–102]. However, DCs depending on their morphological and phenotypic subtypes can either induce anti-tumor immune responses or promote tumor growth and progression [103]. The crosstalk of tumor with their TME is a crucial factor which results in the development of cancer [104]. Along this line, it has been described that high extent of expression of the chemokine (C-X-C motif) ligand 1 (CXCL1) by tumor and stromal cells can promote CSCs/CICs survival and proliferation and attract at tumor site DCs with suppressive functions, that could correlate tumor progression and poor survival of patients [104].
Macrophages represent important players for innate immune responses and can act as APCs similarly to DCs [105]. Based on their phenotype and functions they can be distinguished in two subpopulations: 1. The M1 subtype that are characterized by elevated pro-inflammatory cytokines, such as IL-12, IL-1β, IL-6, and tumor necrosis factor α (TNF-α), increased expression of HLA class II molecules, generation of reactive oxygen and nitrogen intermediates and ability to induce TH1-type T cell responses [106]. 2. In the presence IL-4, IL-10, and IL-13, macrophages can polarize towards M2 phenotype. These cells express scavenging, mannose and galactose receptors, IL-10, vascular endothelial growth factor (VEGF), matrix metalloproteinases (MMPs) and activation of the arginase pathway, leading to pro-tumoral effects [105–107, 109]. The cross-talk between CSCs/CICs and TAM is orchestrated by STAT3 signaling [102, 103]. Upon iper-modulation of STAT3 in TAM, they can promote stemness, survival and proliferation in cancer cells while the latest cells can induce the immunosuppressive properties of TAM, leading to the impairment of cancer immune-surveillance [110].
Myeloid derived suppressor cells (MDSCs) are immune cells endowed with suppressive functions that can inhibit the effector functions of immune responses [111]. The frequency of these cells either at tumor site or in the circulation has been described as a prognostic factor for patients’ survival as well as of responsiveness to immunotherapy [112]. Interestingly, STAT3 can lead the differentiation of monocytes towards MDSCs in pancreatic tumors [113] regulating also the development of CSCs/CICs [113]. The secretion of pro-inflammatory cytokines and chemokines by tumor cells can induce the differentiation and recruitment of immunosuppressive cells that can also contribute to sustain the inflammatory TME and to the interaction and reciprocal influence of CSCs/CICs and their niche [110, 113–115]. Another key regulator of the cross-talk between CSCs/CICs and TAM and DCs is represented by CD47 [116]. This molecule is over-expressed by CSCs/CICs of B cell malignancies. The binding of this molecule to the signal regulatory protein alpha (SIRPα), that mediates phagocytic functions in DCs and macrophages, has been shown to mediate the impairment of innate responses [116]. The cross-talk between CSCs/CICs and myeloid cells can affect both the fate and immunological profile of these cells, with implications for their susceptibilities to immune responses. Further studies should be designed to dissect the interactions of CSCs/CICs with different immune cells, although the major limitation is represented by the lack of in vivo models to monitor the interaction of these different immune cell population in the context of TME…
CONCLUSIONS Recent advances in the genomic, molecular and immunological profiling of CSCs/CICs have contributed to the identification of dysregulated molecular pathways that orchestrate stem-like cancer cells and their interaction with TME. The heterogeneity and plasticity of these cells and the mutual effect of TME and CSCs/CICs on the resulting anti-tumoral or pro-tumoral environment, represent the principle limitations in predicting the fate of these cells and their role in cancer patients’ outcome. In addition, these cells have been identified as key players in therapeutic resistance of tumors and in the development of their dormancy. The down-modulation of HLA molecules and NK activatory ligands on CSCs/CICs, through decreasing their susceptibility to T or NK cell targeting, might represent one of the principle factors leading to resistance to immunotherapy. Although, the mechanisms regulating the levels of HLA molecules and NKG2D ligands on CSCs/CICs are yet to be dissected. Due to the complexity of the cross-talk between CSCs/CICs and TME and the high plasticity of these cells, it is difficult to predict what type of immune cells could play a relevant role in targeting CSCs/CICs. Multifactorial investigations, including the immunological profile, immunomodulating molecules, the interaction with TME and the type of immune cell infiltration will allow to provide insights. Nevertheless, the available tools to isolate and characterize CSCs/CICs, such as spheroids, immunodeficient mice, antigenic profile, are unsatisfactory to dissect the cross-talk of these cells with TME. Moreover, the development of pre-clinical in vivo models engrafted with human immune system is desirable to allow the monitoring of the interaction of CSCs/CICs with TME.
The targeting of CSCs/CICs by immunotherapy could result in the complete tumor eradication and stable clinical responses in cancer patients. This goal could be achieved by the design of combination of strategies based on innate and/or antigen-specific T cell responses with immunoregulatory agents that can render CSCs/CICs susceptible to cell-mediated immunosurveillance. In cases where epigenetic factors are responsible for low antigen presentation, the usage of demethylating agents could represent a potential strategy to overcome the low expression of HLA molecules.
Molecular approaches dissecting the fate of CSCs/CICs within tumor tissues will allow to develop immune-based precision medicine approaches and to identify biomarkers predictive of patients’ responsiveness to therapies.