Bruschini S.

Ciliberto G.

Mancini R.

English

Archivio della ricerca- Università di Roma La Sapienza

Bruschini et al. Cell Death and Disease          (2020) 11:471 https://doi.org/10.1038/s41419-020-2669-8 Cell Death & DiseaseCOMMENT Open Ac ce s sThe emerging role of cancer cell plasticity andcell-cycle quiescence in immune escapeSara Bruschini1, Gennaro Ciliberto 2 and Rita Mancini3Molecular programs that control the function and thephenotype of stem cells are also active in cancer andconfer properties that promote progression and resistanceto therapy. Likewise, the specific properties that enablelong-lived stem cells to evade immune surveillance can beco-opted by latent cancer cells responsible for tumourinitiation as well as metastatic outbreak. Following theclinical success of anticancer immunotherapy in recentyears, greater focus has been placed on the interplaybetween cancer cells and the tumour immune micro-environment. However, the link between stem-cell-liketumour phenotype and the immunological properties ofcancer has not yet been systematically explored. Newevidence discussed in this article, stemming fromsophisticated approaches that make use of lineage tracingand single-cell analysis, provide strong proof of a linkbetween cancer stem cells, tumour cell plasticity, cell-cycle quiescence and immune suppression in cancer1.The concept that the immune system may have a pro-tective role in tumour development found its roots in theimmunosurveillance hypothesis by Burnet and Thomas2,3.New experimental data led to incorporating this hypoth-esis into the broader immuno-editing concept that con-sists in three phases: elimination, equilibrium and escape4.Along this view, the immune system exerts both host-protecting and tumour-sculpting effects and the pressureexerted by cancer immunosurveillance’s arsenal (i.e.elimination phase), together with the genetic instability oftumours, lead to an equilibrium phase. During this phasethe best-fitting cancer cells, subjected to Darwinianselection, can lead to escape and the appearance of aclinically detectable disease4.In the last few years, we have witnessed remarkable pro-gress in the field of cancer immunology and today many ofthe mechanisms that tumours use to prevent clearance bythe immune system have been revealed. However, the earliestevents of immune evasion are not yet known. A set of recentstudies showed that cancer stem cells (CSCs) have the abilityto hide from the immune system ab initio, evading form theimmunosurveillance phase. Agudo et al.5 showed that theimmune privilege of epithelial stem cells is associated withtheir proliferative state and is not an inherent property theystably possess. To determine the interactions of T cells withadult tissue stem cells, in their niche, the authors injected inthe Lgr5-GFP mice, Jedi (just EGFP death-inducing) T cells,which express a TCR specific for an immunodominant epi-tope of green fluorescent protein (EGFP), or control T cellsas well as GFP (to activate Jedi T cells). Through using thisclever approach, the authors showed that fast cycling stemcells, such as Lgr5+ stem cells in the gut, ovaries andmammary gland were subjected to immune clearance. Incontrast, slow-cycling stem cells, such as those in hair folli-cles and muscle, were resistant to Jedi T-cell killing. Fur-thermore, immune escape depends on an intrinsic propertyof quiescent stem cells, which undergo a cell autonomousdownregulation of the antigen presentation machinerymediated by the transactivator NLRC5. Notably, the processis reversible when stem cells enter the cell cycle. In addition,in ex vivo experiments, quiescent stem cells appear to beprotected also from NK cell killing.This ability of long-lived stem cells to evade immunesurveillance is probably due to their critical role in themaintenance of tissue homeostasis. As CSCs can derive fromnormal stem cells, these findings suggest that CSCs may bethe earliest cancer cells that evade immune surveillance, co-opting properties of quiescent stem cells. In this regard,Malladi et al.6 showed that the latency and immune evasion© The Author(s) 2020OpenAccessThis article is licensedunder aCreativeCommonsAttribution 4.0 International License,whichpermits use, sharing, adaptation, distribution and reproductionin any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate ifchangesweremade. The images or other third partymaterial in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to thematerial. Ifmaterial is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtainpermission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.Correspondence: Gennaro Ciliberto (gennaro.ciliberto@ifo.gov.it)1Department of Experimental and Clinical Medicine, Magna Graecia Universityof Catanzaro, 88100 Catanzaro, Italy2Scientific Directorate, IRCSS Regina Elena National Cancer Institute, 00128Rome, ItalyFull list of author information is available at the end of the article.Official journal of the Cell Death Differentiation Association1234567890():,;1234567890():,;1234567890():,;1234567890():,;of metastatic cancer cells is strictly correlated with theacquisition of a slow-cycling stem-cell-like state. Theresearchers created a new metastatic model through inject-ing, in athymic mice, GFP-labelled lung and breast cancercells and the subsequent isolation, after 3 months, in differentorgans of the mice of what they called latency competentcancer cells (LCC). By gene-set-enrichment analysis, theauthors revealed that these cells show stem-like phenotype,express SOX2 and SOX9 transcription factors, and self-impose a slow-cycling state by the autocrine production of aWNT inhibitor, DDK1. Upon entering quiescence LCC cellsevade NK-mediated immune surveillance through a broaddownregulation of ULBP NK cells activators. In the proposedmodel, after infiltrating target organs, LCC proliferating cellsare killed by NK cells, but a minority of them enter aquiescence state and remain latent for an extended time. Assuch, they retain a metastasis-initiating power as shown byNK depletion, a condition that may mimic a transientdecrease in immune surveillance.Hence, the immune privileged status is not an intrinsicproperty of CSCs, but is linked to the ability to enter aquiescent condition. This was best demonstrated in a veryrecent study by the Massague’s lab1 in which through the useof single-cell RNA sequencing it was possible to identify inmetastatic lesion of lung adenocarcinomas, cell subpopula-tions with different stem grading, depending on SOX2 andSOX9 expression ranging from adult stem cells state, inter-mediate regenerative subpopulations right through toalveolar proliferative progenitors. Taking advantage of thepreviously described LCC mouse model the authorsdemonstrated a developmental-stage-specific sensitivity toNK cells during the metastatic outbreak, suggesting CSCplasticity, that governs the ability to switch from one devel-opment program to another, as an alternative weapon toescape from NK cells and to survive (Fig. 1).As CSCs are considered a subpopulation of tumour cellswith enhanced capacity of self-renewal, metastatic dis-semination and resistance to conventional treatment7,8,the studies discussed above explain in part how they mayachieve these features. However, they do not specificallyaddress issues related to resistance to immunotherapy. Inthis respect, Miao et al.9 showed that, in small-cellFig. 1 Quiescent cancer stem cells (CSCs) are able to evade immune surveillance and to promote tumour development. At the site of theprimary tumour, differentiated cancer cells and proliferating clusters of CSCs are subjected to immune cells clearance, instead CSCs that enter in aquiescent state are hidden. Isolated quiescent CSCs can enter the bloodstream and, evading the surrounding immune cells, are able to exit fromdormancy and colonize the metastatic site. Metastatic outbreak can occur thanks to CSC plasticity and the acquisition of new immune evasivemechanisms. Like other types of treatments, CSCs are also refractory to immunotherapies leading to tumour relapse. These resistant cells overexpresskey antigens or metabolic vulnerabilities that can be targeted by newer CSCs-specific immunotherapies or drugs directed to CSCs-associatedpathways. Immunotherapies could be combined with targeted CSCs agents to both debulk the original tumour and eradicate any emerging resistantcells. However, the optimal timing, sequence and combination of these CSCs-specific, immune-based therapies requires further studies.Bruschini et al. Cell Death and Disease          (2020) 11:471 Page 2 of 3Official journal of the Cell Death Differentiation Associationcarcinoma (SCC), the TGF-β-responding CSCs, known tosurvive chemotherapy, are also refractory to adoptive T-cell transfer (ACT)-based-immunotherapy and areresponsible for tumour relapse. Establishing a novelmouse SCC model in which neoantigen expression iscoupled with oncogene activation and using lineage tra-cing, they identified a novel resistance mechanism to ACTtherapy, that is not due to neoenatigen editing. In essence,employing single-cell RNA-Seq and in vitro co-cultureanalyses, the authors revealed that these CSCs selectivelyexpress the CD80 surface ligand that, upon engagingCTLA4 on T cells, mediates the exhaustion of theircytotoxic activity, after ACT treatment. The phenomenonis reversed upon CTLA4 or TGF-β-blocking immu-notherapies, paving the way for a combination approach.From the perspective that CSCs are not only the earliestbut also the most resilient immune evaders, there is com-pelling urgency to identify approaches that selectively targetthis subpopulation of tumour cells. The main challenge inthe CSCs research remains their isolation. Since the firstpostulation of their existence10, major efforts have beendirected towards identifying specific surface as well asmetabolic markers to discriminate between bulk tumour cellsand CSCs. An example is represented by the increased lipiddesaturation, sustained by SCD1 enzyme, in the stem-cellpool that has been proven in different tumour types11,12. Inthis framework, the specific interactions between CSCs andimmune environment could also be exploited for detectionand study of CSCs, a new approach adopted by Paczullaet al.13. These authors have identified AML stem cells byscreening patients with acute myeloid leukaemia (AML) forexpressing NKG2D ligands, known to be able to activate NKcells. The subset of NKG2DL-negative cells displayedmolecular and functional properties of stem cells, and theability to repopulate immunodeficient mice as well as tosurvive to chemotherapy in PDX models. Mechanistically inthese cells high expression of PARP1 is responsible for therepression of NKG2DL, which mediates evasion from NKcells clearance. Moreover, pharmacologic inhibition ofPARP1 resensitizes AML cells to NK cell killing in immu-nocompromised mice injected with human NK cells.These findings, as well as those previously discussed,highlight the critical interplay between key signallingpathways crucial for stem-cells propagation and themechanisms that guide immune evasion. Clinically this setof evidences open the intriguing perspective that ther-apeutic agents capable of targeting signalling pathwaysresponsible for cell entry into quiescence could be com-bined with immunotherapies, based on the ability to har-ness the power of immune system to fight cancer cells14(Fig. 1). In conclusion, a deeper understanding of theunique interactions between cancer stem cells and theimmune system and the development of more sophisticatedexperimental systems could provide ground for the estab-lishment of therapeutic strategies aiming to harness theimmune system against the “hardest immune-evaders”.AcknowledgementsThe work has been partially supported by Italian Association for CancerResearch (AIRC) grants IG15216 and IG19865 to G. Ciliberto and IG17009 to R.Mancini and by the Lazio Innova grant 2018 n. 85-2017-13750 to R. Manciniand PRIN Bando 2017 (Prot. 2017HWTP2K) to G. Ciliberto and R. Mancini. Themanuscript has been partially supported by the co-funding of Unione europea—FESR o FSE, PON Ricerca e Innovazione 2014–2020. We thank Tania Merlinofor English language editing of the manuscript.Author details1Department of Experimental and Clinical Medicine, Magna Graecia Universityof Catanzaro, 88100 Catanzaro, Italy. 2Scientific Directorate, IRCSS Regina ElenaNational Cancer Institute, 00128 Rome, Italy. 3Department of Clinical andMolecular Medicine, Sapienza University of Rome, 00161 Rome, ItalyConflict of interestThe authors declare that they have no conflict of interest.Publisher’s noteSpringer Nature remains neutral with regard to jurisdictional claims inpublished maps and institutional affiliations.Received: 6 May 2020 Revised: 27 May 2020 Accepted: 29 May 2020References1. Laughney, A. M. et al. Regenerative lineages and immune-mediated pruningin lung cancer metastasis. Nat. Med. 26, 259–269 (2020).2. Burnet, M. Cancer—a biological approach I. The Processes of control. Br. Med.J. 1, 779–786 (1957).3. Thomas, L. Cellular and Humoral Aspects of the Hypersensitive States (Hoeber-Harper, New York, 1959) pp. 529–533.4. Dunn, G. P., Bruce, A. T., Ikeda, H., Old, L. J. & Schreiber, R. D. Cancer immu-noediting: from immunosurveillance to tumor escape. Nat. Immunol. 3,991–998 (2002).5. Agudo, J. et al. Quiescent tissue stem cells evade immune surveillance.Immunity 48, 271–284.e6 (2018).6. Malladi, S. et al. Metastatic latency and immune evasion through autocrineinhibition of WNT. Cell 165, 45–60 (2016).7. Batlle, E. & Clevers, H. Cancer stem cells revisited. Nat. Med. 23, 1124–1134(2017).8. Pisanu, M. E. et al. Inhibition of Stearoyl-CoA desaturase 1 reverts BRAF andMEK inhibition-induced selection of cancer stem cells in BRAF-mutatedmelanoma. J. Exp. Clin. Cancer Res. 37, 1–17 (2018).9. Miao, Y. et al. Adaptive immune resistance emerges from tumor-initiatingstem cells. Cell 177, 1172–1186 (2019).10. Lapidot, T. et al. A cell initiating human acute myeloid leukaemia aftertransplantation into SCID mice. Nature 367, 645–648 (1994).11. Noto, A. et al. Stearoyl-CoA-desaturase 1 regulates lung cancer stemness viastabilization and nuclear localization of YAP/TAZ. Oncogene 36, 4573–4584(2017).12. Li, J. et al. Lipid desaturation is a metabolic marker and therapeutic target ofovarian cancer stem cells. Cell Stem Cell 20, 303–314.e5 (2017).13. Paczulla, A. M. et al. Absence of NKG2D ligands defines leukaemia stem cellsand mediates their immune evasion. Nature 572, 254–259 (2019).14. Clara, J. A., Monge, C., Yang, Y. & Takebe, N. Targeting signalling pathways andthe immune microenvironment of cancer stem cells—a clinical update. Nat.Rev. Clin. Oncol. 17, 204–232 (2020).Bruschini et al. Cell Death and Disease          (2020) 11:471 Page 3 of 3Official journal of the Cell Death Differentiation Association

The emerging role of cancer cell plasticity and cell-cycle quiescence in immune escape

https://iris.uniroma1.it/bitstream/11573/1427656/1/Bruschini_Emerging_2020.pdf

The emerging role of cancer cell plasticity and cell-cycle quiescence in immune escape

Abstract

Similar works

Full text

Available Versions

Archivio della ricerca- Università di Roma La Sapienza