Does Cancer Weaken The Immune System – Cancer stem cells (CSCs) are subsets of undifferentiated cancer cells within the tumor mass that are responsible for tumor initiation, recurrence, and treatment resistance. The increased ability of CSCs to give rise to new tumors suggests a potential role for these cells in evading immune surveillance. A growing body of evidence describes interactions between CSCs and immune cells within the tumor microenvironment (TME). Recent data have demonstrated the key role of some key immune cells in driving the expansion of CSCs, which simultaneously trigger evasion of detection and destruction by various immune cells through a number of different mechanisms. Here, we will discuss the role of immune cells in driving cancer cell metastasis and provide evidence of how CSCs evade immune surveillance by exerting their effects on tumor-associated macrophages (TAMs), dendritic cells (DCs), suppressive myeloid-derived cells. (MDSCs), T regulatory (Treg) cells, natural killer (NK) cells and tumor infiltrating lymphocytes (TIL). Knowledge gained from interactions between CSCs and various immune cells will provide insight into how tumors evade immune surveillance. Finally, CSC-targeted immunotherapy is emerging as a new strategy for cancer immunotherapy by disrupting the interaction between immune cells and CSCs in the TME.
Cancer stem cells (CSCs) are subsets of cancer cells enriched with stem cell-like properties, including self-renewal capacity and multilineage differentiation (Bhatia and Kumar, 2016). The CSC theory of tumor progression depicts the tumor microenvironment (TME) as a hierarchically organized tissue with CSC subsets at the highest level, generating more differentiated cancer cells with reduced or limited proliferative capacity. CSCs are often defined by the expression of stem cell surface markers such as CD24, CD34, CD44, CD47, CD133 and CD90, along with subsets that can be isolated and enriched in vitro and in vivo without stem cell surface markers (Taniguchi et al., 2019). Epigenetic-to-mesenchymal transition (EMT) is known to induce CSC phenotypes through epigenetic regulation (Bocci et al., 2019). Its activation allows CSCs to develop resistance to conventional therapy, thus leading to treatment relapse and tumor recurrence (Shibue and Weinberg, 2017).
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Does Cancer Weaken The Immune System
A large body of literature has detailed the interaction of tumor masses with the immune system; However, research has only begun to elucidate the relationship between CSCs and immune cells within the TME, paving the way for the development of rational therapeutic strategies to probe CSC immune function. Tumor initiation competence of CSCs in partially immunosuppressed mice, e.g. SCID or NOD/SCID mice (T, B cell defects but NK cells present) suggests that these cells have a certain ability to evade immune detection and surveillance, but non-CSCs require a greater deficiency of the immune system to form tumors in NSG mice (T, B and NK cells deficient) (Tsuchiya and Shiota, 2021). Growing evidence has shown that there is a reciprocal interaction between CSCs and various immune cells. Sequestered immune cells within the TME drive CSC expansion and simultaneously induce immune cell initiator activity, promoting CSC-specific evasion of immune detection and destruction. In this section, we will discuss new knowledge about the role of tumor-associated macrophages (TAM), dendritic cells (DC), myeloid-derived suppressor cells (MDSC), T-regulatory (Treg) cells, natural killer (NK) cells. , and tumor-infiltrating lymphocytes (TILs) to drive cancer stemness and how CSCs evade the immune surveillance of these cells. Finally, we will discuss the potential of CSC-targeted immunotherapy to eradicate cancer.
The History And Advances In Cancer Immunotherapy: Understanding The Characteristics Of Tumor Infiltrating Immune Cells And Their Therapeutic Implications
Macrophages can be classified into two subtypes: pro-inflammatory M1 and anti-inflammatory M2 macrophages (Chen et al., 2019). TAMs typically express the M2 phenotype, which has immunosuppressive and tumor suppressor activity and is therefore closely related to cancer progression and recurrence (Lewis and Pollard, 2006; Malfitano et al., 2020).
New findings support the hypothesis that CSCs influence the immune TME by recruiting macrophages and promoting their tumorigenic properties, while TAMs are crucial for the self-renewal and maintenance capacity of CSCs in primary tumors through a link between STAT3 and NF-κB. (Sainz et al., 2016). It has been suggested that CSCs have an intrinsic immunosuppressive program that involves the recruitment of macrophages and their targeting to M2 polarization at the tumor site (Brissette et al., 2012). This ability of CSCs is commonly found in ovarian, glioblastoma, liver, breast and lung cancers through activation of the signal transducer and activator of transcription 3 (STAT3) and nuclear factor-kB (NF-kB) pathways and cytokines such as interleukin (IL)-8 and IL-10 (Iliopoulos et al., 2009; Ginestier et al., 2010; Mitchem et al., 2013; Fang et al., 2014). For example, in hepatocellular carcinoma (HCC), CD133
Cells induce M2 TAM polarization through IL-8 secretion (Xiao et al., 2018). In glioblastoma, CSCs produce higher levels of the chemoattractants C-C motif chemokine ligand 2 (CCL2), CCL5, vascular endothelial growth factor-A (VEGF-A), and neurotensin than bulk glioma (Yi et al., 2011). The extracellular matrix protein periostin is preferentially expressed on CD133
Glioma CSCs and recruits macrophages through integrin αvβ3 from peripheral blood to the brain (Zhou et al., 2015). Depletion of periostin in glioma CSCs leads to a decrease in the M2 population and reduces tumor growth in glioblastoma xenografts. In breast cancer, Sox2
Immune Responses Elicited By Ssrna( ) Oncolytic Viruses In The Host And In The Tumor Microenvironment
Cancer cells, through the activation of nuclear factor of activated T cells (NFAT), STAT3 and NF-κB, express the chemokines CCL3 and ICAM-1, thus recruiting TAMs to the TME (Yang et al., 2013; Mou et al. , 2015). These results suggest that CSCs play an important role in TAM recruitment and M2 polarization by secreting macrophage chemokines.
After recruitment of TAMs to TMEs, TAMs are used as a “niche” to support CSC growth. Infiltrating TAMs, by activating the NF-κB signaling pathway, secrete the inflammatory cytokines IL-1β, IL-6, IL-10, transforming growth factor beta (TGF-β), and MFG-E8 ( Jinushi et al., 2011 ; Li et al. et al., 2012; Fang et al., 2014; Wan et al., 2014; Yang et al., 2019). These tumor-promoting cytokines bind to their receptors and further stimulate STAT3 activation in nearby CSCs. This results in a vicious cycle of NF-κB activation as well as maintenance of cancer cells. For example, treatment of breast cancer cells with TAM conditioned medium leads to upregulation of the stem cell markers Sox-2, Oct3/4 and Nanog with increased ALDH1 activity in a mouse model (Nnv and Kundu, 2018). Knockdown of STAT3 confirmed the role of the JAK/STAT pathway in mediating TAM regulation of CSC enrichment. In co-culture systems, recruited TAMs promote liver CSC expansion through IL-6/STAT3, Wnt/β-catenin and TGF-β signaling pathways (Fang et al., 2014; Wan et al., 2014; Chen et al.. , 2019). TAMs preferentially secrete TGF-β to induce CSC-like properties by inducing EMT, whereas TAM-derived IL-6 induces CD44
Expansion of HCC stem cells through STAT3 activation and thus promotes tumor progression through CSC growth. Blockade of IL-6 with tocilizumab and STAT3 knockdown attenuated CD44
Spherogenesis and tumor growth of patient-derived HCC as well as breast resection (Wan et al., 2014; Wang et al., 2018a).
T Cell Transfer Therapy
CSCs via EphA/ephrin A signal and promote tumorigenesis in breast cancer tissue (Lu et al., 2014). The EMT program first induces the expression of the surface ligands Thy1 and EphA4, which enable more frequent cell-cell communication between TAMs and CSCs. Regulated TAM-CSC contact thus activates the EphA4 receptor on CSCs and its downstream Src and NF-κB pathways (Iliopoulos et al., 2009; Lu et al., 2014). Activation of NF-κB positively increases the secretion of cytokines, including IL-6, IL-8, and GM-CSF, which are important for CSC self-renewal and stemness maintenance (Rinkenbaugh and Baldwin, 2016; Choi et al., 2019). Interestingly, proinflammatory M1 macrophages were also found to play a role in breast CSC formation through their activation of the STAT3 and NF-κB pathways by CD44
Cells (Guo et al., 2019). There is a possibility that M1 macrophages, through M2-mediated signaling, direct CSC formation and control tumorigenesis. Other signaling pathways, such as PTN/β-catenin, Notch1, and p38-MAPK, are also involved in stimulating CSC self-renewal in lymphoma, lung cancer, and ovarian cancer through the preferential secretion of IL-10 and IL-17 by TAMs. (Xiang et al., 2015; Wei X. et al., 2019; Yang et al., 2019). Collectively, TAMs, through activation of the STAT3 and NF-κB signaling cascades and the cytokines IL-1β, IL-6, IL-8, IL-10 and IL-17 and the growth factor TGF-β, play an important role in themselves. – recovery and chemoresistance of CSCs.
Numerous studies have demonstrated the direct regulation of CSC self-renewal and proliferation by TAMs. CSCs also take advantage of the immunosuppressive activity of TAMs to evade immune surveillance. In HCC, TAMs provide a “safe” environment for CSCs by overexpressing SIPRα, which interacts with CD47 which in turn acts as a “Don’t eat me” signal and protects CSCs from phagocytosis. Recently, CD24, one of the CSC markers in the liver, was identified as another “Don’t eat me” signal to macrophages by binding to the inhibitory receptor that binds sialic acid-like lectin-like 10 (Siglec-10) (Lee et al. . ., 2014; Barkal et al., 2019). Hepatic CSCs can also avoid macrophage clearance by interacting with their surface receptor Siglec-10. TAMs also influence the cytotoxic activity of T cells by inducing immune regulatory molecules such as programmed cell death ligand 1 (PD-L1) in cancer cells and T-cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), a programmed cell death protein- 1
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