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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 modu- lating 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. . . . Keywords Cancer stem cells/Cancer initiating cells Immunosurveillance Adaptive immune responses Innate immune . . responses Tumor microenvironment Immunotherapy Abbreviations IL-4 Interleukin 4 ALDH Aldehyde dehydrogenase IL-10 Interleukin 10 APC Antigen presenting cells IL-13 Interleukin 13 APM Antigen processing machinery IL-13α2 α2 chain of IL-13 receptor CAR Chimeric antigen receptor mAb Monoclonal antibody; CIC Cancer initiating cell MDSC Myeloid derived suppressor cell CRC Colorectal cancer NSCLC Non-small cell lung cancer CT Cancer testis PD-1 Programmed death 1 CTLA-4 Cytotoxic lymphocyte antigen-4 PD-L1 Programmed death ligand 1 CSPG4 Chondroitin sulphate protidoglycan 4 RCC Renal cell carcinoma HLA Human leukocyte antigen STAT3 Signal transducer and activator of transcription 3 IDO Indoleamine 2,3-dioxygenase TGFB Transforming growth factor beta GBM Glioblastoma multiforme TAA Tumor associated antigen GDF-15 Growth differentiation factor-15 Treg T regulatory cell. IFN Interferon Introduction Shilpa Ravindran and Saad Rasool contributed equally to this work. Tumors are composed by heterogeneous cellular components * Cristina Maccalli including a rare subpopulation bearing “stemness properties” firstname.lastname@example.org and being responsible of tumor initiation and progression. These cells have been denominated cancer stem cells Research Department, Sidra Medicine, Al Luqta Street, PO Box 26999, Doha, Qatar (CSCs) or cancer initiating cells (CICs) [1–6]. CSCs/CICs 134 Ravindran S. et al. share several characteristics with normal stem cells, such as detecting the presence of these cells within tumor lesions the ability to self-renew and to give rise to differentiated prog- though probing for CSC/CIC- associated markers has not pro- eny and the resistance to DNA damage-induced cell death [3, vided conclusive results. The xenotransplantation in immune 5–12]. CSCs/CICs, through the cycling from proliferation to deficient mice represents a useful tool to demonstrate in vivo quiescence, expression of ABC drug pumps, high levels of the tumorigenic properties CSCs/CICs . Xenograft anti-apoptotic proteins and resistance to DNA damage, are models have contributed to prove the existence within tumor resistant to radiation and chemotherapy and play an important lesions of cell population endowed with stemness properties role in disease relapse and tumor progression [13, 14]. that upon serial transplantation could propagate both tumori- CSCs/CICs have been isolated from both hematological genic CSCs/CICs and malignant cells with differentiated phe- and solid tumors and they represent a rare subpopulation, notype without tumorigenic properties . These subpopu- comprising 0.01–10% of cells within the tumor . They lations can be identified only through transplantation in im- can be ex vivo identified based on their “stem cell-like” char- mune deficient mice [4, 36–38]. acteristics and the expression of certain cell surface and func- Nevertheless, the available CSC/CIC-associated tional markers . The identification of CSCs/CICs was first markers are dependent on spatial and temporal features, reported in leukemia, showing a hierarchical organization of with their modulation occurring in relation to their inocu- tumor cells . The leukemic cells were able to be engrafted lation in immunodeficient mice, proving the high level of + − upon transplantation of CD34 CD38 cells into severe com- plasticity of these cells and that none of the available bined immune-deficient (SCID) mice, which eventually led to markers can be exploited to monitor the in vivo fate of the identification of the hierarchical organization of tumors these cells [1, 39, 40] CSCs/CICs, similarly to normal stem with few cells endowed with stemness and tumorigenic prop- cells, require a “niche” to allow the survival of these cells erties . Since then, a variety of studies highlighted the and their cycling from quiescence to proliferation and to existence of “stem-like” cancer cells in solid tumors with dif- maintain stemness and multipotency [41–43]. The “niche” ferent histological origins [5, 18–23]. Multiple molecules is represented by the tumor microenvironment (TME), (e.g., ALDH-1, CD133, CD44, CD24, CBX3, ABCA5, which is composed of multicellular and dynamic compart- LGR5, etc) have been identified as CSC/CIC-associated ments that include fibroblasts, endothelial, stromal, mesen- markers with differential expression depending on the tissues chymal and immune cells . The interaction of TME of derivation, highlighting the high grade of heterogeneity of with stem-like cancer cells can regulate the fate of these these cells (Table 1). Most of these molecules are over- cells through modulating the proliferation, differentiation, expressed by CSCs/CICs but are also shared with either dif- immunological properties and resistance to therapies ferentiated tumor cells or normal stem cells [4, 34]. As a result, [44–50]. Table 1 Markers expressed by Marker Tumor type Recognition by T Reference CSCs/CICs isolated from solid cells tumors and their role as TAAs ALDH1 CRC; breast and gastric cancer; melanoma √  CD133 GBM, pancreas, lung, ovarian, prostate, and gastric √ [25–27] cancer CD44 CRC, head and neck cancer EpCAM CRC, Retinoblastoma  EpCAM CD44 Pancreatic cancer CD24 CD24 CRC √ [29, 30] SOX2 GBM √  CBX3 Ostocarcinoma LGR5 CRC ABCB5 Melanoma CD90 Liver cancer HSP DNAJB8 RCC √ [32, 33] CD166 CRC; NSCLC a b Markers commonly identified as associated with CSCs/CICs; the role of these antigens in eliciting T cell- mediated immune responses against CSCs/CICs CRC: colorectal cancer; GBM: glioblastoma multiforme; NSCLC: non-small cell lung cancer; RCC: renal cell carcinoma The Cross Talk between Cancer Stem Cells/Cancer Initiating Cells and Tumor Microenvironment: The Missing... 135 The high grade of heterogeneity and plasticity of and of the “niche”, preventing the constant monitoring of CSCs/CICs can depend on their tissue of derivation and, plasticity and heterogeneity of these cells (Figs. 1, 2). importantly, on their cross-talk with TME [4, 16, 51–53]. Therefore, the combination of deep genomic, molecular Limiting the isolation and the functional characterization and functional profiling of CSCs/CICs could represent a rele- of CSCs/CICs to the usage of phenotypic markers is un- vant method to achieve a comprehensive functional character- satisfactory and do not consider the possibility that ization of these cells and, possibly, of their role in tumor out- “stemness” function of tumor cells can be reversible, as come . shown by Quintana et al. for melanoma [1, 39]. Moreover, CSCs/CICs have been identified as the tumor compo- xenotransplantation of these cells in immune deficient nents responsible for resistance to standard therapy, as mice is lacking the important variable of the TME and well as immunotherapy [10, 57–60]. Although clinical its role in affecting the fate of CSCs/CICs . responses in cancer patients are observed following Therefore, the lack of standardized methods to isolate treatments, these cells can remain in the minimal resid- CSCs/CICs and of in vivo models allowing to monitor ual disease and upon changes in the environment they the cross-talk of these cells with TME can lead to the high can exit the quiescence status and give rise to novel extent of variability in assessing the functional properties malignant lesion(s) or even initiate the metastatic colo- of thesecells andinpreventingtoaccuratelydetermine nization [8, 61–63]. their fate and role in the tissue of origins and in the clin- The extensive molecular and immunological characterization ical outcome of cancer patients [54, 55]. The tool of of CSCs/CICs is warranted in order to understand the mecha- sphere forming assay to propagate in vitro CSCs/CICs is nisms regulating their plasticity, quiescence, interaction with the too simplified, lacking the important component of TME TME and resistance to therapies and to immune responses. Fig. 1 Differential immunogenic profile by CSCs/CICs vs. bulk tumor by CSCs/CICs. Neoantigens, generated by somatic mutation bearing tu- cells. CSCs/CICs can express defective levels of HLA molecules and mor cells are equally expressed by both CSCs/CICs and differentiated APM components leading to low immunogenicity and escape from im- tumor cells. The latest TAAs represent highly immunogenic target mole- mune responses. In the presence of efficient expression of ligands of NK- cules, since they are not expressed by normal cells. APM: antigen pro- associated activatory receptors, these cells can become susceptible to NK cessing machinery; CSCs/CICs: cancer stem cells/cancer initiating cells; cell recognition. Moreover, TAAs can be expressed at suboptimal levels NK: natural killer cells 136 Ravindran S. et al. Fig. 2 Immunotherapy strategies to target CSCs/CICs. An overview of multiple immunotherapy approaches or with standard therapies warrant immunotherapy approaches including adoptive cell therapy with either 1. further investigation to assess the efficacy in increasing the immunoge- TCR or CAR engineered T lymphocytes; 2. Immune check point nicity of CSCs/CICs and to implement the targeting of these cells by blockade with mAbs; 3. Cancer vaccination with TAAs expressed by immune responses. CSCs/CICs: cancer stem cells/cancer initiating cells; both CSCs/CICs and differentiated tumor cells; 4. Innate immune re- TAA: tumor associated antigen sponse or 5. γδ T cell recognition of tumor cells. Combination of either Immunological Profile of CSCs from CRC and endowed with stemness properties, showed detectable level of HLA class I molecules as well susceptibil- HLA Molecules and APM Components ity to antigen-specific cytotoxic T lymphocytes (CTLs) , however this study has been performed using long-term The expression of HLA class I and class II molecules in vitro established cell lines, that could have lost phenotypic and APM has been investigated in CSCs/CICs isolated from properties of primary CSCs/CICs. Indeed, stem-like cells iso- colorectal cancer (CRC) and glioblastoma multiforme (GBM) lated by sphere-forming assay displayed aberrant expression showing an overall aberrant expression of these molecules, of HLA class I and APM components [16, 65]. Contradictory with, in some cases, failure in their modulation by the pre- results were obtained also in glioblastoma multiforme (GBM); treatment with IFNs (both alpha and gamma) or DNA CSCs/CICs isolated as sphere forming cells from this tumor demethylating agent (5-Aza CdR) [64, 65]. This impairment have been shown to exhibit the expression of HLA class I in antigen processing and presentation by CSCs/CICs lead, molecules  while, when applying these analyses to prima- upon co-culture of these cells with autologous T cells, to a ry GBM-derived sphere forming cells, defective expression of preferential selection and differentiation of TH2 type T cells HLA class I and APM molecules was detected . Stem-like and failure in eliciting effector functions [64, 65]. The subop- cells expressing ABCB5 and isolated from melanoma were timal expression of HLA class I molecules and APM compo- found to express suboptimal levels of HLA class I molecules nents was also reported in CSCs/CICs isolated from different while they were positive for HLA class II (45). APM compo- type of solid tumors [64–69]. These peculiar observations nents (e.g., LMP2, LMP7 MECL-1, TAP1 and TAP2) detect- suggested that the defective expression of HLA molecules ed through mRNA analyses were found to be expressed in could represent a tool for the identification of CSCs/CICs tumor sphere-models from different solid malignancies, . On the contrary, the side population (SP) cells derived representing a tool for in vitro enrichment of stem-like cells The Cross Talk between Cancer Stem Cells/Cancer Initiating Cells and Tumor Microenvironment: The Missing... 137 and for the investigation of micro-metastasis . However, They are categorized into three groups; (i) the HLA class I and class II molecules were down-modulated in overexpressed/self-antigens that are expressed at high these cells as compared to differentiated tumor cells, also fol- levels by tumor cells and detectable, although at lower lowing their pre-treatment in vitro with IFN-γ, highlighting an levels, on normal tissues (e.g., MART-1/Melan-A, impairment of antigen presentation by these cells . It hTERT, EGFR, survivin). (ii) Cancer testis (CT) antigens needs to be considered that this study did not analyze the that are detectable on tumor cells and not on normal cells, expression at protein levels of APM molecules, therefore except for testis and trophoblast (e.g., NY-ESO1, MAGE post-transcriptional mechanism could affect their expression. A3-A4, PRAME, CT83, SSX2). (iii) Neoantigens or mu- Moreover, long term in vitro established cell lines were used tated antigens derived by non-synonymous mutations in to isolate tumor cell spheres while in other studies reporting cancer cells (e.g., MUM-1, CDK4, ME1, ACTN4, HLA- defective expression of APM components, primary CSCs/ A2) . The neoantigens are higher immunogenic com- CICs have been investigated. These examples highlight that pared to differentiation/self TAAs since are tumor specific an overall suboptimal immunogenic potency by CSCs/CICs and do not induce tolerogenic mechanisms in immune resulting in low or impaired susceptibility to T cell mediated cells [83–85]. Neoantigens have been shown to drive im- immune responses (Fig. 1). This represents a mechanisms of mune responses and to mediate efficient T cell recognition evasion by immune responses that is shared with normal stem of tumor cells, leading to cancer eradication in patients cells, that could represent a typical feature of cells with treated with either mutanome based vaccines or adoptive stemness properties . Importantly, the failure in the ex- cell therapy (ACT) with tumor infiltrating lymphocytes pression of HLA molecules by tumor cells was found as one [84–86]. Notably, CSCs/CICs bearing a somatic mutation of the mechanisms of failure of the clinical activity of immune in the CRC-associated “driver” gene SMAD4, could elicit checkpoint blockade agents in cancer patients [75, 76], indi- antigen-specific T cell responses directed to both stemness cating that either CSCs/CICs can display immune evasion and differentiated components of tumor . mechanisms shared by differentiated tumor cells or that in- A transcriptome analysis of the SP cells and main popu- deed the suboptimal expression of HLA molecules of these lation (MP) derived from CRC, breast and lung cancer re- cells and their resistance to T cell recognition can protect these vealed a preferential expression of 18 CT antigens cells from immunotherapy interventions, leading to tumor re- (MAGEA2, MAGEA3, MAGEA4, MAGEA6, MAGEA12, currence or progression. However, the lack of standardization MAGEB2, GAGE1, GAGE8, SPANXA1, SPANXB1, in methods for both, the isolation of cells with stemness prop- SPANXC, XAGE2, SPA17, BORIS, PLU-1, SGY-1, erties and to analyze HLA and APM molecules, represents a TEX15 and CT45A1) in CSCs/CICs . The TAA limitation in providing conclusive results. Nevertheless, de- DNAJB8, that is a member of the heat shock protein tailed analysis to identify the molecular mechanisms that lead (HSP) 40 family, was found to be preferentially expressed to aberrant expression of HLA molecules and APM compo- in renal cell carcinoma (RCC); interestingly this protein nents are warranted. played an important role in the maintenance of The suboptimal expression of HLA class I molecules if CSCs/CICs. DNAJB8-specific immune responses could be associated with detectable NKG2D ligands, can drive the in- detected in a mice model study of DNA vaccination for creased susceptibility of CSCs/CICs to Natural Killer (NK) RCC, rendering this molecule appealing for targeting cells. This phenomenon has been observed in CSCs/CICs CSCs/CICs by the immune system [32, 33](Table 1). from glioma, melanoma, and CRC [68, 77–79]. However, Recently a new antigen, Ankyrin repeat and SOCS box pro- down-modulation of NKG2D ligands on CSCs/CICs has been tein 4 (ASB4), was described as target molecule of CTLs documented, e.g., in GBM patients suggesting thatthe recognizing CSCs/CICs and not the differentiated cellular expression of low levels of NK cell activating ligands can components of the tumor . Suboptimal expression of result in the impairment of anti-CSCs/CICs innate immune TAAs (MART-1, ML-IAP, NY-ESO-1, and MAGE-A) was responses (Fig. 1). The expression profile of molecules acti- reported in melanoma-derived CSCs/CICs (Fig. 1). vating innate immune responses on CSCs/CICs can be affect- Similar results were obtained in CSCs/CICs isolated from ed by their crosstalk with TME, and thus, by their plasticity GBM and CRC (Fig. 1 and Table 1)[64, 65]. On the other that can influence the fate in vivo of these cells. hand, CD133 CSCs/CICs isolated from melanoma were shown to express either NY-ESO-1 or DEAD/H (Asp-Glu- Tumor Associated Antigens and Adaptive Immune Ala-Asp/His) box polypeptide 3, X-linked (DDX3X) Responses against CSCs/CICs representing target of tumor-specific T cells [90, 91]. Other studies have described the isolation of T lymphocytes rec- Tumor associated antigens (TAAs) can be recognized by ognizing TAAs expressed by CSCs/CICs such as IL-13Rα2, T lymphocytes when exposed on the surface of tumor SOX2 and CD133 in GBM, CEP55 and COA-1 in CRC and cells in the form of peptide/HLA complexes [80, 81]. EpCAM in retinoblastoma (Table 1)[28, 65, 71, 92]. 138 Ravindran S. et al. Innate Immune Responses and their Relationship characterized by elevated pro-inflammatory cytokines, such with CSCs/CICs as IL-12, IL-1β, IL-6, and tumor necrosis factor α (TNF-α), increased expression of HLA class II molecules, generation of Natural killer (NK) cells are the first line of defense against reactive oxygen and nitrogen intermediates and ability to in- cancer development and metastasis. NK cells have been de- duce TH1-type T cell responses . 2. In the presence IL-4, scribed to efficiently recognize and kill in vitro CSCs/CICs iso- IL-10, and IL-13, macrophages can polarize towards M2 phe- lated from CRC, melanoma and glioblastoma [68, 78, 93, 94]. notype. These cells express scavenging, mannose and galac- The efficiency of NK cell-mediated lysis of CSCs/CICs was tose receptors, IL-10, vascular endothelial growth factor dependent on the expression of NCR ligands (NKp30 and (VEGF), matrix metalloproteinases (MMPs) and activation NKp44), NKG2D ligands and when suboptimal or negative ex- of the arginase pathway, leading to pro-tumoral effects pression of HLA class I molecules were found on the surface of [105–107, 109]. The cross-talk between CSCs/CICs and CSCs/CICs (Fig 1)[68, 78, 93–95]. Tallerico et al. found that TAM is orchestrated by STAT3 signaling [102, 103]. Upon CSC/CIC but not their differentiated counterpart of CRC is sus- iper-modulation of STAT3 in TAM, they can promote ceptible to NK cells . Similar results have been reported in stemness, survival and proliferation in cancer cells while the GBM and melanoma, highlighting that the amount of ligands of latest cells can induce the immunosuppressive properties of activatory NK receptors on CSCs/CICs was determinant for ef- TAM, leading to the impairment of cancer immune- ficient innate immune responses [68, 77, 78]. In patients with surveillance . acute myeloid leukemia (AML), the suboptimal expression of Myeloid derived suppressor cells (MDSCs) are immune cells NKG2D ligands has been described as a mecahnisms of escape endowed with suppressive functions that can inhibit the effector by tumor cells from NK cell recognition , confirming that functions of immune responses . The frequency of these these molecules can affect the susceptibility of cancer cells to cells either at tumor site or in the circulation has been described innate responses. The observations that NKG2D ligands could as a prognostic factor for patients’ survival as well as of respon- represent as biomarkers for prediction of clinical responses to siveness to immunotherapy . Interestingly, STAT3 can lead immune checkpoint blockade in melanoma highlight that the the differentiation of monocytes towards MDSCs in pancreatic pattern of NKG2D ligands expression by tumor cells can affect tumors  regulating also the development of CSCs/CICs the type and efficiency of elicited anti-tumor immune responses . The secretion of pro-inflammatory cytokines and . Therefore, the levels and pattern of expression of NKG2D chemokines by tumor cells can induce the differentiation and ligands by tumor cells, including CSCs/CICs could be a predic- recruitment of immunosuppressive cells that can also contribute tive marker for the choice of the type of immunotherapy to sustain the inflammatory TME and to the interaction and re- interventions. ciprocal influence of CSCs/CICs and their niche [110, 113–115]. Dendritic cells (DCs) are antigen presenting cells (APCs) Another key regulator of the cross-talk between CSCs/CICs and that can activate either innate or adaptive immune responses TAM and DCs is represented by CD47 . This molecule is . In addition, they play an important role in the formation over-expressed by CSCs/CICs of B cell malignancies. The bind- of anti-tumor T- and B cell immunologic memories . ing of this molecule to the signal regulatory protein alpha Immature DCs can capture the tumor-derived antigens by (SIRPα), that mediates phagocytic functions in DCs and macro- phagocytosis or pinocytosis and then migrate to lymphoid phages, has been shown to mediate the impairment of innate organs where they present these TAAs in the form of HLA/ responses . The cross-talk between CSCs/CICs and mye- peptide complexes to T cells, resulting in antigen-specific im- loid cells can affect both the fate and immunological profile of mune responses [100–102]. However, DCs depending on these cells, with implications for their susceptibilities to immune their morphological and phenotypic subtypes can either in- responses. Further studies should be designed to dissect the in- duce anti-tumor immune responses or promote tumor growth teractions of CSCs/CICs with different immune cells, although and progression . The crosstalk of tumor with their TME the major limitation is represented by the lack of in vivo models is a crucial factor which results in the development of cancer to monitor the interaction of these different immune cell popula- . Along this line, it has been described that high extent of tion in the context of TME. 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 Immunomodulatory Properties of CSCs/CICs with suppressive functions, that could correlate tumor pro- gression and poor survival of patients . The immunological profiling of CSCs/CICs has revealed that Macrophages represent important players for innate im- they share some characteristics with embryonic, hematopoiet- mune responses and can act as APCs similarly to DCs . ic and mesenchymal stem cells displaying immunoregulatory Based on their phenotype and functions they can be distin- functions that render these cells invisible to immune responses guished in two subpopulations: 1. The M1 subtype that are and able to escape from tumor immune responses [4, 74, 117]. The Cross Talk between Cancer Stem Cells/Cancer Initiating Cells and Tumor Microenvironment: The Missing... 139 The principle mechanisms governing the immunomodulation inhibition of T cell effector functions (Table 2)[65, 135]. It of CSCs/CICs are described below. has been demonstrated that the over-expression of IL-4 by CRC-derived CSCs/CICs has led to inefficient TCR- mediated proliferation and antigen recognition of CTLs . Cytokines, Chemokines, Growth Factors & Immune Interestingly, the neutralization of this cytokine by mAb could Checkpoint Molecules overcome the T cell mediated anti-tumor impairment and in- duce antigen-specific recognition of both CSCs/CICs and dif- The observations that CSCs/CICs isolated from different tu- ferentiated tumor cells . This study showed that, upon up- mor types can secrete soluble factors, such as Galectin-3, regulation of HLA class I and APM expression through IFN-γ GDF-15, IL-10, IL-13, PGE2 and TGFb, or express treatment of CSCs/CICs, T cells could specifically recognize a immune checkpoint molecules with immunosuppressive func- neoantigen, SMAD4, generated by a non-synonymous muta- tions, have suggested that these cells can regulate the impair- tion bearing stem-like cells and bulk tumor cells . Thus, ment of immune responses as well as regulating a pro-tumoral CTL reactivity against CSCs/CICs and the TAA-specific TME (Table 2)[4, 51, 18–130]. These immunosuppressive immunosurveillance could be improved by the usage of strat- factors have been described to induce the differentiation of egies to correct the low immunogenic profile of these cells. regulatory T cells (Tregs) or MDSCs and M2 macrophages, The immune suppressive profile of CSCs/CICs has been resulting in the impairment of effector functions of innate and also confirmed by evidences describing the expression by adaptive responses [4, 51, 130, 131]. Moreover, pro- these cells of immune checkpoint molecules (e.g. CTLA-4, inflammatory cytokines such as IL-6, IL-8, IL-10 and IL-13, PD-L1, B7-H3 or B7-H4) (Table 2)[4, 34, 64, 65, 136]. released by CSCs/CICs can contribute to maintain an inflam- These observations highlighted the similarities between matory and suppressive TME representing the “niche” sus- CSCs/CICs and normal stem cells in terms of the immune taining cellular stemness (Table 2)[132, 133]. Indoleamine profile [34, 137, 138]. Moreover, altered expression of 2,3-dioxigenase (IDO), that mediates the catabolism of tryp- STAT3 pathway in CSCs/CICs can also affect their immune tophan, has been shown to be expressed by CSCs/CICs, con- suppressive activity through inhibiting T cell proliferation and tributing to the differentiation of Tregs, skewing the cytokine activation, inducing the differentiation of Tregs and triggering profiling of T cells toward TH2 -type and inhibiting the sur- Tcell apoptosis . The observations reported above show vival and proliferation of CTL (Table 2)[133, 134]. that multiple mechanisms and molecular pathways are either In addition, the CSC/CIC-associated expression of IL-4 up-regulated or aberrantly activated in CSCs/CICs resulting in and CD200, through cell-to-cell interaction, lead to the Table 2 Immunomodulatory molecules detected in CSCs/CICs a b Molecule Function Activity in CSCs/CICs Reference IL-4 Cytokine involved in differentiation of Inhibition of TH1 cell mediated immune responses. [65, 118] naïve T cells to Th2. IL-10, IL-13 Anti-inflammatory cytokines Suppression of CTL functions; differentiation of [89, 119] Tregs and MDSCs TGFB Growth factor with potent inhibitory function Tregs differentiation, inhibition of TH1 responses [89, 120] STAT3 Transcription factor with a potential Maintenance and proliferation of CSCs/CICs; differ- [115, 121] anti-inflammatory function entiation of MDSCs, iDCs, M2 GDF15 Growth and differentiation factor Inhibition of anti-tumor immune responses  related to cellular stress. Galectin-3 Protein with important role in cell-cell Inhibitor of T cell mediated immune responses [89, 123] adhesion and interactions with the extracellular envi- ronment. IDO Enzyme involved in tryptophan catabolism Suppression of TH1 type immune responses and [34, 51, 64, 65, 123] differentiation of Tregs. CD200 A glycoprotein that regulates myeloid cell activity and Immune suppression and regulation of anti-tumor [124, 125] inhibits macrophage lineages. activity. PD-L1 Ligand of PD-1 and Immune checkpoint molecule Inhibition of CTL immune responses. [64, 65, 126, 127] B7-H3 and Immune checkpoint molecules Immunomodulation of cellular immune responses [34, 64, 65, 128, 129] B7-H4 : function of the molecules listed in the Table : Activity of these molecules when expressed by CSCs/CICs iDC: suppressive dendritic cell; MDSC: Myeloid derived suppressive cells; M2: M2 phenotype of monocytes/macrophages; TH1: T helper type 1; TH2: T helper type 2 140 Ravindran S. et al. their immune suppressive properties, therefore the blockade of high levels of PD-L1 and contain Tregs, M2 like macrophages these signaling through the combination of inhibitory agents as well as exhausted T cells . CSCs/CICs that are con- should be considered in order to rescue the tumor-specific sidered the architects of their own microenvironment , as immune responses. well as generated by epithelial-to-mesenchymal transition (EMT) can be potentially responsible for the type of immune MicroRNAs infiltration depending of their pattern of immune profile. Common gene expression patterns have been found in miRNAs are non-coding RNAs regulating at post- normal mammary stem cells and dormant tumor cells transcriptional levels, through complementary binding to tar- from breast cancer suggesting the possible presence get mRNA, the expression of genes . The altered regu- of stem-like cells in dormant tumors . In addition, lation of gene expression in tumor cells can occur by both up- different cell sub-populations could be isolated from re- or down regulation of miRNA . The most common ac- lapsed AML endowed with differential tumorigenic abili- tivity of miRNAs in CSCs/CICs is represented by the control ty depending on their up-regulation of stemness signaling of the expression of either oncogenes (e.g., MiR34a, MiR31 . or MiR205) or tumor suppressor genes . The aberrant A better understand of the relationship between stemness expression of few miRNAs, such as miRNAs 451and 199b- properties, immunological profile of CSCs/CICs and tumor 5p, has been shown to affect stem-like cell properties isolated dormancy will provide insights on the mechanisms of thera- from different type of tumors (e.g., GBM, breast cancer and peutic resistance of these cells and will allow to identify strat- medulloblastoma) [139–143]. Of note, miRNAs displaying egies for complete tumor eradication. regulatory activity on immune-related genes (e.g, miRNA- 199a that can regulate the IFN-mediated responses) can play a role in the differentiation of mammalian CSCs/CICs . Immunological Targeting of CSCs/CICs The level of miRNA-124, through regulating the expression of STAT3, can affect the efficiency of anti-CSC/CIC T cell Cancer Vaccines responses in GBM . Along this line, miR203 and miR92 can control the stemness and immunological profiles The recognition of TAAs expressed by CSCs/CICs by T cells of melanoma cells [146, 147]. have been documented (see Table 1). These in vitro or in vivo models were based on the usage of TAAs that represented sources of antigens for the therapeutic administration of can- Immune Evasion and Tumor Dormancy cer vaccines in cancer patients . However, the principle limiting factor of the clinical efficacy of this strategy is repre- Tumor dormancy is represented by quiescent cells that can sented by the usage of “self”/tolerogenic TAAs, shared with remain occult and undetectable by regular diagnostic methods normal tissues . The low or negative expression of these for long intervals of time, even after initial clinical responses categories of antigens and of CT-TAAs by CSCs/CICs can to therapies . Quiescence of cells is the ability to exit cell represent an additional reason of failure of high rate and long cycle and remain in G0 phase until permissive environmental duration of clinical responses observed in cancer patients condition will lead to enter back into the cycling phase. This is treated with cancer vaccines [4, 34]. In addition, the sub- considered one of the principle mechanisms underlying tumor optimal levels of HLA class I molecules and APM by stem- dormancy. CSCs/CICs display the ability to cycle between like cells can drive the failure in targeting CSCs/CICs by quiescence and proliferation and together with their resistance cancer vaccines leading to the development of tumor dorman- to therapies represent the link between these cells and tumor cy and tumor recurrence, although the observance of initial dormancy [2, 5, 8, 9, 149–151]. Furthermore, the immune clinical efficacy of these therapeutic interventions [4, 34]. suppressive mechanisms associated with CSCs/CICs can or- DC-based vaccines, exploiting these cells as APC to pres- chestrate the evasion of these cells from immune recognition ent TAAs to T cell-mediated responses, represent also a ther- and immunosurveillance, and could be considered additional apeutic strategy for cancer patients showing encouraging clin- factors responsible of tumor dormancy . ical activity [102, 156–162]. DCs loaded with either CSC/ An important mechanisms of immune-surveillance is the CIC-lysates or mRNA isolated from these cells represented homing of immune cells to the tumor site, which ultimately source of antigens for vaccination in the context of Phase I/ form the immune infiltrate. Tumors arising from epithelial II clinical trials of GBM patients [163, 164]. These studies breast cancer are known to possess high levels MHC class I provided proof of principle of improved overall survival of molecules and of infiltrating T effector cells and M1 macro- cancer patients treated with CSC/CIC targeted immunothera- phages. The immune infiltrate from mesenchymal like breast py [163–165]. Immune responses, with, in some cases in- cancer tumors exhibit low levels of MHC class I molecules, creased frequency of circulating NK cells, were detected in The Cross Talk between Cancer Stem Cells/Cancer Initiating Cells and Tumor Microenvironment: The Missing... patients showing clinical benefit from these treatments [163, GBM [34, 64, 65, 177–179]. ,CSCs/CICs could theoretically 165]. Of note, these therapeutic interventions could overcome be targeted in vivo by immune checkpoint blockade agents, the failure of CSCs/CICs in expressing efficient levels of HLA enhancing the clinical efficacy of cancer vaccines, as demon- class I molecules and in presenting TAAs to T cells, strated in a mouse model . However, recent reports de- documenting for the first time, that cancer vaccine, if eliciting scribing that clinical failure of these therapies was associated NK cell-mediated responses, could target stem-like with defective expression of HLA class I molecules by tumor tumor cells [158, 163–165]. Tumor cell clones expressing cells [75, 76], suggest that these cells might evade from the immunogenic neoantigens can undergo immune selection ICB-mediated unleash of immune responses (Fig. 2). due to the recognition and elimination by T lymphocytes, leading to the survival of tumor cell clones not expressing Adoptive Cell Therapy strong immunogenic antigens and maintaining the expression of low immunogenic TAAs  (and see https://www. ACT is represented by the isolation of T lymphocytes from biorxiv.org/content/10.1101/536433v1). This process is also cancer patients, their ex vivo expansion, and the infusion back associated with immune evasions mechanisms developed by into patients [181–183]. In addition, T lymphocytes both tumor cells and TME . engineered to express TCR with high affinity for a cognate In some tumors, the decrease in antigen presentation is a TAA could be exploited for ACT studies . Highly en- result of epigenetic silencing of the genes involved in antigen couraging and sustained responses mediated by adoptively presentation machinery. The usage of demethylating agents transferred TCR targeting the TAA NY-ESO-1 have recently such as 5-Aza-2′-deoxycytidine to reduce the methylation of been reported in different tumor types, such as breast cancer genes involved in antigen presentation, is a potential strategy and myeloma [86, 184]. Nevertheless, the antigen choice is to increase the antigen presentation in these CSC/CICs. The highly relevant to prevent severe toxicities due to “off-target” effect of demethylation has been shown in CSCs/CICs from cross-reaction with normal tissues sharing the same antigens breast cancer, where it resulted in high expression levels of or expressing molecules mimicking the TAAs . TAP1, which is involved in antigen presentation . Neoantigens have been described as candidate TAAs effi- In addition, increased antigen presentation also improves ciently recognized by T cells that can be exploited for ACT of the potential of discovering novel antigens, which can then be cancer patients and, interestingly, CTL targeting these anti- helpful in development of new anti-cancer vaccines (Fig. 2). gens could be isolated from tumor infiltrating lymphocytes (TILs) of melanoma and other type of malignant lesions Immune Checkpoint Blockade [183, 185, 186]. Nevertheless, ACT to target neoantigens can represent a promising approach for treatment of cancer Immune checkpoints, including CTLA-4, PD-1 and PD-L1, patients upon assessment of HLA expression by both CSCs/ are important physiological regulators of innate and adaptive CICs and differentiated tumor cells and, in case of suboptimal immune responses . Biological inhibitory agents have levels of expression, the achievement of their up-regulation by been clinically developed, revealing striking therapeutically pre-treatment with immunomodulating agents [4, 34, 51]. success [169–175]. However, a significant proportion of can- T cell can be genetically modified to express a chimeric cer patients failed to benefit from these therapies. antigen receptor (CAR) that is composed of epitope-specific The effectiveness of immune checkpoint blockade domains isolated from mAbs linked to T cell-derived (ICB) is largely dependent on the tumor microenviron- activatory/costimulatory molecules [182, 187–189]. CAR-T ment . Tumors such as melanoma, bladder cancer cells can recognize TAAs independently on the expression and non-small cell lung cancer (NSCLC) can be charac- of HLA molecules and APM components . CAR-T cell terized as “hot” tumors due to their inflamed TME, high therapy for some subgroups of hematological malignancies levels of and neo-antigen expression and of T cell infil- represent the salvage intervention leading to stable clinical tration and detection of PD-L1. These tumors have been responses and improved overall survival of patients refractory reported to be associated with higher frequency of suscep- to standard therapies or with recurrences [187, 189–192]. The tibility to immune checkpoint treatments. On the other usage of CAR-T cell therapy for solid tumors is currently hand, prostate cancer is considered to be a “cold” tumor, under investigation, showing encouraging results in cancer due to minimal level of T cell infiltration, and limited patients with aggressive tumor types, including malignant me- response to single agent checkpoint inhibition . sothelioma, pancreatic cancer and GBM [193–197]. Expression of immune checkpoint molecules has been ob- CAR-T cells targeting TAAs, such as CD133, EGFRvIII, served in CSCs/CICs from different histological origins . EpCAM, CSPG4 and B7-H3, expressed by different type of PD-L1 expression was detected at high levels in CSCs/CICs solid tumors, including CSC/CIC components, have been de- isolated from primary human head and neck squamous cell veloped in pre-clinical studies [196–201]. These studies have shown that the targeting of TAAs that are expressed only by carcinoma (HNSCC), gastric and breast cancer, CRC and Ravindran S. et al. tumor cells, including CSCs/CICs, and not by normal cells, human immune system is desirable to allow the monitoring could provide the rational for safe and efficient clinical devel- of the interaction of CSCs/CICs with TME. opment of CAR-T cells therapy for these tumors(Fig. 2)[200, The targeting of CSCs/CICs by immunotherapy could re- 202]. Moreover, the combination of CAR-T cells targeting sult in the complete tumor eradication and stable clinical re- dual TAAs, EGFRvIII and CD133, has been used for the sponses in cancer patients. This goal could be achieved by the successful therapeutic treatment of a patient with advanced design of combination of strategies based on innate and/or cholangiocarcinoma . antigen-specific T cell responses with immunoregulatory CAR-T cells targeting NKG2D ligands on CSCs/CICs agents that can render CSCs/CICs susceptible to cell- have been investigated and tested both in vitro and in vivo mediated immunosurveillance. In cases where epigenetic fac- [204, 205]. CSCs/CICs from glioblastoma expressing detect- tors are responsible for low antigen presentation, the usage of able NKG2D ligands could be efficiently targeted by CAR- T demethylating agents could represent a potential strategy to cells. These tools showed to efficintly eliminate also xenograft overcome the low expression of HLA molecules. tumors . Nevertheless, a major limitation associated with Molecular approaches dissecting the fate of CSCs/CICs the use of these CAR-T cells is represented by the variability within tumor tissues will allow to develop immune-based pre- of the levels of NKG2D ligands on the surface of CSCs/CICs, cision medicine approaches and to identify biomarkers predic- depending on their origin and methodology used for their tive of patients’ responsiveness to therapies. ex vivo isolation. Acknowledgements This study was supported by Qatar National Nevertheless, further investigations aimed at a comprehen- Research Fund, grant no. NPRP10-0129-170277. sive genomic and immunological characterization CSCs/CICs are warranted to implement the efficiency and safety of ACT Funding Information Open Access funding provided by the Qatar strategies. National Library. Compliance with Ethical Standards Conclusions Conflict of Interest All the authors have no conflict of interest to disclose. Recent advances in the genomic, molecular and immunolog- ical profiling of CSCs/CICs have contributed to the identifi- Open Access This article is distributed under the terms of the Creative cation of dysregulated molecular pathways that orchestrate Commons Attribution 4.0 International License (http:// stem-like cancer cells and their interaction with TME. The creativecommons.org/licenses/by/4.0/), which permits unrestricted use, heterogeneity and plasticity of these cells and the mutual ef- distribution, and reproduction in any medium, provided you give appro- priate credit to the original author(s) and the source, provide a link to the fect of TME and CSCs/CICs on the resulting anti-tumoral or Creative Commons license, and indicate if changes were made. pro-tumoral environment, represent the principle limitations in predicting the fate of these cells and their role in cancer patients’ outcome. 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