Maccalli-2018-The role of cancer stem cells in.pdf

Contents lists available at ScienceDirectSeminars in Cancer Biologyjournal homepage: role of cancer stem cells in the modulation of anti-tumor immuneresponsesCristina Maccallia,Kakil Ibrahim Rasulb,Mamoun Elawadc,Soldano FerronedaClinical Research Center,Translational Medicine,Sidra Medicine,Doha,QatarbHaemtology and Oncology Department,National Center for Cancer Care and Research(NCCCR),Hamad Medical Corporation,Doha,QatarcGastroenterology,Hepatology and Nutrition Department,Sidra Medicine,Doha,QatardDepartment of Surgery,Massachusetts General Hospital,Harvard Medical School,Boston,MA,USAA R T I C L E I N F OKeywords:Cancer stem cellsImmunological profilingImmune escape mechanismsTumor dormancyImmune-based interventionsA B S T R A C TTumor lesions comprise multiple subpopulations of cells including those endowed with“stemness”properties.The latter cells are responsible of tumor initiation,metastasis formation,resistance to conventional therapies anddisease recurrence.These relatively rare cells denominated cancer stem cells(CSCs)or cancer initiating cells(CICs)are defined based on self-renewing,multipotency and tumorigenicity.These cells through their im-munomodulating features can evade from immunesurveillance,persisting in the form of quiescence and dor-mancy.They can drive the neoplastic growth and recurrence,even after long latency.Moreover,CSCs/CICs dueto their ability to modulate and shape immune responses can represent the component of a tumor causingimmunotherapy resistance in cancer patients.In this review a general overview of immunological properties ofCSCs/CICs is provided,with a special focus on the mechanisms of modulation of T cell mediated responses.Theneed to further dissect the mechanisms regulating the immunological profile of CSCs/CICs and their interactionswith immune cells and tumor microenvironment is discussed.An improved characterization of the im-munological properties of CSCs/CICs will contribute to the rationale design of immunotherapeutic interventionswhich target these cells and may lead to the eradication of malignant diseases.1.IntroductionAs shown for the first time by Thomas and Burnet(Thomas L.,Hoeber-Harper,1959 New York)1,2,the immune system can controltumor growth.The prognostic role of immune responses for cancerpatients has been described 3 and,more recently this concept hasbeen validated by the association of nature,location and density oftumor-infiltrating lymphocytes(TILs)with clinical outcome in color-ectal cancer(CRC)patients 4,5.The concept of“immunoscore hasbeen created to classify CRC patients based on the extent of immune cellinfiltrate;it represents a more informative prognostic biomarker thanthe traditional TNM staging in CRC patients 510.Nevertheless,avariety of adaptive phenomena can shape the tumor-immune cell in-terplay enabling a dynamic equilibrium state in which cancer cells cansurvive in a dormant state 11.The immune system can eliminatetumor cells while subsequently can maintain them in a state of equili-brium or,upon the induction of immune evasion mechanisms in tumormicroenvironment(TME),resulting in its impairment and tumor pro-gression.These phases of anti-tumor immune responses have beendenominated the three“Es”theory of cancer 12.Additionally,tumorcells adapt to survive in a hostile immune microenvironment by de-veloping mechanisms which reduce their immunogenicity 13.Anti-tumor immune responses can also select immune-resistant tumor cells,that will not be eliminated by cognate tumor antigen-specific T cellsand by NK cells,resulting in tumor immunoediting 12.This scenariocan be described as immune system-mediated tumor dormancy,inwhich tumor cells can evade immune responsiveness through either theactivationofintrinsicmechanismsortheshapingofanim-munosuppressive TME.Advances in immunotherapy have lead to the development oftherapeutic strategies aimed at inducing systemic tumor antigen-spe-cific immune responses 1418.Importantly,the clinical developmentof immune checkpoint inhibitors which unleash tumor antigen-specificT cells has changed the paradigm of cancer therapy 1924.However,a significant proportion of patients is unresponsive or develops re-sistance to these therapeutic strategies.Tumor lesions are composed of cell subpopulations heterogeneousfor genetic,phenotypic and functional properties,that can differ inhttps:/doi.org/10.1016/j.semcancer.2018.09.006Received 19 June 2018;Received in revised form 12 September 2018;Accepted 17 September 2018Corresponding author at:Clinical Research Center,Division of Translational Medicine,Sidra Medicine,Al Luqta Street,PoBox 26999,Doha,Qatar.E-mail address:cmaccallisidra.org(C.Maccalli).Seminars in Cancer Biology 53(2018)189200Available online 24 September 20181044-579X/2018 Elsevier Ltd.All rights reserved.Ttheir ability to generate and propagate tumors as well as in their sus-ceptibility to therapeutic interventions.A minor subpopulation is re-presented by cancer stem cells or cancer initiating cells(CSCs/CICs)which are endowed with high-rate self-renewal,multi-potency and tu-morigenicity 2531.These cells have been identified as responsible ofmetastatic spread,tumor recurrence,therapy resistance and diseaseprogression 32,33.CSCs/CICs are likely to play a crucial role incancer patients immune and clinical responses to immunotherapy.The efficient targeting of CSCs/CICs could contribute to the eradi-cation of the component of the tumors endowed with quiescence,therapeutic resistance and dormant phenotype,all of which sustainlong-term maintenance and progression of tumors.For this reason,themolecular heterogeneity,plasticity and evolution of genetic,pheno-typic and immunological dynamic variations of these cells should befully characterized.In this review we first describe the immunologicalproperties of CSCs/CICs and the experimental evidence documentinghosts immune responses against these cells,with major emphasis on Tcell mediated responses.Then we review the immune evasion me-chanisms utilized by CSCs/CICs;we emphasize their role in mediatingthe impairment of cancer immunesurveillance,and as possible me-chanisms governing tumor dormancy.Lastly,we discuss the im-munotherapeutic approaches and their combinations to overcome im-munomodulation mediated by CSCs/CICs.2.Biological properties of CSCs/CICsCancer cells with“stemness”properties have been isolated frommany hematological and solid tumors with different histological origins3438.These cells can be isolated ex vivo and their CSC/CIC prop-erties can be characterized based on their self-renewal,multipotencydifferentiating into cell lineages of the tissues of origin and tumor-igenicity in immune deficient mice 29,3941.Therefore,they sharesome similarities with normal stem cells.The intrinsic“stemness”properties of these cells,through replication,can perpetuate CSC/CICsubpopulations and generate all the differentiated cell types that com-pose a tumor bulk 42.The first report of CSC identification occurredfor hematological malignancies,showing a hierarchical organization oftumor cells 35,43.Engraftment of leukemic cells could successfullyoccur only upon transplantation of CD34+CD38cell fractions leadingto the identification of stem-like cancer cells in leukemia 35,43.In-terestingly,this tumor model provided the opportunity to extensivelyinvestigate the functional behavior of different leukemic cell sub-populations.These studies showed that pluripotent CSCs have a veryslow cycling rate while differentiated bulk tumor cells mostly generatehighly dividing cells 44.CSC/CIC tumorigenic properties have been shown through xeno-transplantation in immune deficient mice 42.These models havedemonstrated that upon transplantation,cells with“stemness”proper-ties can give rise to tumors resembling the original malignancies 41.Xenograft assays have been used also to demonstrate the hierarchicalorganization of solid tumors,leading to the identification of tumori-genic populations,that upon serial transplantation could generate tu-mors comprising tumorigenic“stem-like cells”and phenotypically di-verse non-tumorigenic cells 34.These subpopulations with distinctfunctional properties cannot be discriminated based on morphologicalcriteria,although upon transplantation in immunodeficient mice cellswith“stemness”properties can give rise to tumors that recapitulate theheterogeneity of the original tumor lesions.Common motif of CSCstudies is represented by the isolation from tumor tissues of rare cellsbased on the expression of single or multiple markers.Upon trans-plantation in immunodeficient mice these cells display tumorigenicproperties,although with variable efficiency,indicating that indeedthese cells are endowed with CSC/CIC properties 29,36,45,46.The hierarchical organization of tumor cells has been clearly foundin hematologicalmalignancies whereCSCs/CICs have been un-doubtedly isolated based on the expression of specific markers.Morecontroversial is the characterization of CSCs/CICs in solid tumors.Manylines of evidence have shown that differentiated tumor cells can de-differentiate into multipotent cells with“stemness”properties 47.Nevertheless,progress in the biological characterization of CSCs/CICshas highlighted high grade of heterogeneity,depending on their tissuederivation and on their plasticity 29,39,40,48,49.Plasticity of CSCs/CICs has been shown in melanoma,where individual cancer cells sortedon the basis of CD133 expression can generate tumors in im-munodeficient mice with similar frequency as CD133cells 50,51.Similarly,differential expression of demethylase has been associatedwith variable tumorigenicity of melanoma cells;however the expres-sion of this marker was observed to be modulated in xenograft tumorsindependently on its expression by the tumor cells injected into im-munodeficient mice 52.Nevertheless,the lack of standardization ofmethods and reagents to isolate CSCs can also affect the high extent ofvariability of tumorigenic assays.One of the variables influencing functional properties and highplasticity of CSCs/CICs is represented by their interactions and cross-talk with TME.Changes in TME can influence also the fate and biolo-gical properties of CSCs/CICs,since it comprises the“niche”needed fortheir maintenance and survival 37,5359.Multiple cell surface makers,e.g.,CD24,CD44,CD133,CD166,Lgr5,etc.,have been found to be expressed by cancer cells with“stemness”properties,depending on their histological origins 29,40(Table 1).Because of their plasticity and continuous evolution in re-lationship with TME interplay CSCs/CICs can modulate the expressionof some“bona fide”CSCs markers 60,61.Most of the markers used toisolate and functionally characterize cells with“stemness”propertiesare overexpressed by these cells and shared with differentiated cellularcounterparts 29,39,40,42(Table 1).CSCs-associated markers,such asaldehyde dehydrogenase isoform 1(ALDH1),CD44v6 and Lgr5,havebeen used either to isolate cells with“stemness”behavior from humantumor tissues or to localize these cells within neoplastic malignancies6265.In some cases,the identification of cells expressing thesemarkers in tumor tissues has been claimed to be correlated with dis-easeprognosis 6265.The usage of CSC/CIC-associated surfacemarker expression as a probe to detect these cells in human tumors andto investigate their impact on the fate of neoplastic lesions,has yieldedinconclusive results.Whether this reflects the modulation of the phe-notype of these cells along with changes in TME 66,67 and/or the lackof standardization of the reagents and methodology used to identify andisolate CSCs/CICs remains to be determined.In this regard,it is usefulTable 1Markers associated with CSCs/CICs.MarkeraTumor typeCD34/CD38AMLCD34/CD38/CD19;CD34/CD38/CD19LeukaemiaALDH1AML;colorectal,breast,gastric and ovarian cancer;melanomaCD133Brain,colorectal,pancreatic,lung,ovarian,prostate,liver and gastric cancerEpCAMliver and colorectal cancerCD44colorectal and head and neck cancerCD24breast,pancreatic and colorectal cancerCBX3-ABCA5osteosarcomaLGR5colorectal cancerABCB1,ABCB5,ABCG2melanomaCD271melanomaSOX10melanoma and pancreatic cancerCD166Colorectal cancer,NSCLC erCD90Liver cancerDNAJB8Renal cell and colrectal cancerAML:acute myeloid leukemia;NSCLC:non-small cell lung cancer.aCSCs/CICs-associated markers 29,40,84.C.Maccalli et al.Seminars in Cancer Biology 53(2018)189200190to point out that the field of CSCs/CICs would greatly benefit from anexchange of reagents used to identify these cells and by wet workshopsto compare“under the same roof”methodologies used to identify andcharacterize CSCs/CICs.This type of approach was crucial to unravelthe genetic organization of a very complex system like the HLA system,to dissect the specificity of HLA alloantisera and to define the role of theHLA system in clinical medicine.The epithelial-to-mesenchymal transition(EMT),a developmentalprogram which drives epithelial cells to acquire mesenchymal proper-ties,can be influenced by inflammation and immune responses.Thisprogram that regulates embryogenesis and wound healing,is the mainexample of physiological transdifferentiation and becomes re-activatedin cancer cells,promoting cell migration,cell dissemination and me-tastatic spread 6873.Through EMT epithelial cells acquire stem cellproperties 7175.Interestingly,immune cells can induce EMT in bothbreast and melanoma cells 72,76.Immunoediting can also eitherregulate EMT activation in cancer cells or select cancer cells that havealready undergone EMT process 77.Chronic inflammation in the gutcan promote tissue damages and generation of intestinal fibrosis,whichseems to result from epithelial-to-mesenchymal transition(EMT)7880.The latter phenomenon is determined by the loss of polar-ization and adhesiveness by epithelia cells,and the acquisition of me-senchymal-like/myofibroblast phenotype,with increase of motility andresistance to apoptosis 7880.Patients with inflammatory boweldisease(IBD)have an increased risk of developing CRC depending onthe duration and severity of inflammatory disease.Moreover,IBD-re-lated CRC can display increased resistance to standard therapies andseverity as compared to sporadic CRC.Therefore,this is an interestingmodel where inflammation,EMT and tumorigenesis are strictly related.Many other findings have linked the presence in tissues of inflammatorycells with EMT in tumors 68,77.Consequently immune responses mayplay a determining role in the induction and immune selection of CSCs/CICs depending on the immune permissive or immunomodulatingstatus of the microenvironment.These data altogether emphasize the need to consider CSC/CICplasticity when tracking or identifying these cells based on markerexpression within tumor tissues.To this purpose xenograft models havelimited usefulness since they cannot accurately predict the actual fate ofcells in the tissue of origin and also their interactions with TME.Noavailable evidence demonstrates that the behavior