Munitz, A

Schiavoni, G

Strid, J

Frontiers in Immunology

English

Spiral - Imperial College Digital Repository

Frontiers in Immunology | www.frontiersin.Edited and reviewed by:Catherine Sautes-Fridman,U1138 Centre de Recherche desCordeliers (CRC) (INSERM), France*Correspondence:Giovanna Schiavonigiovanna.schiavoni@iss.itAriel Munitzarielm@tauex.tau.ac.ilJessica Stridj.strid@imperial.ac.ukSpecialty section:This article was submitted toCancer Immunityand Immunotherapy,a section of the journalFrontiers in ImmunologyReceived: 08 November 2021Accepted: 11 November 2021Published: 26 November 2021Citation:Schiavoni G, Munitz A and Strid J(2021) Editorial: Emerging Roles forType 2-Associated Cells andCytokines in Cancer Immunity.Front. Immunol. 12:811125.doi: 10.3389/fimmu.2021.811125EDITORIALpublished: 26 November 2021doi: 10.3389/fimmu.2021.811125Editorial: Emerging Roles forType 2-Associated Cells andCytokines in Cancer ImmunityGiovanna Schiavoni1*, Ariel Munitz2* and Jessica Strid3*1 Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy, 2 Department of ClinicalMicrobiology and Immunology, Tel Aviv University, Tel Aviv, Israel, 3 Department of Immunology and Inflammation, ImperialCollege London, London, United KingdomKeywords: cancer immunity, type 2 associated cells, Th2 cytokines, tumor microenvironment, granulocytesEditorial on the Research TopicEmerging Roles for Type 2-associated Cells and Cytokines in Cancer ImmunityType 2 immune responses have mainly been studied in the context of parasite infections and allergicdiseases. However, emerging evidence suggests important roles for Type 2 immunity in multipleadditional physiological and pathological settings (1). In fact, Type 2-associated cells, such aseosinophils, mast cells, basophils, Type 2 innate lymphoid cells (ILC2), as well as the cytokines IL-4,IL-5, IL-13, IL-33 and thymic stromal lymphopoietin (TSLP) are now considered a significantsignaling and effector cell axis in metabolism, tissue remodeling, neuroinflammation and cancer.This Research Topic collects relevant studies on the emerging role of some Type 2-associated cellsand cytokines in the modulation of cancer progression and anti-tumor immune responses.Among the Type 2 cytokines, IL-33 and TSLP are epithelial-derived alarmins capable ofactivating a plethora of innate and adaptive immune cell populations, thereby affecting tumorimmune control. Some Type 2-associated cells, such as mast cells, eosinophils and basophils, displaypleiotropic activities within the tumor microenvironment (TME). On the one hand, they canprovide growth and angiogenic factors to promote tumor growth. On the other hand, they can exerttumor cytotoxicity through degranulation and release of soluble mediators. In a mini review article,Eissmann et al. debate the role of the IL-33/ST2 axis and mast cells in the regulation ofgastrointestinal cancer. Mast cells can regulate IL-33 bioactivity through the release of tryptaseand chymase that cleave the immature full-length form of IL-33 into the mature form of thecytokine. Several immune cells, including mast cells, express ST2 at various levels on their cellssurface and respond to IL-33 in the TME of gastrointestinal cancers. During pre-cancerousinflammation, a functional cooperation between IL-33 and mast cells promotes the restoration ofthe epithelial barrier and the regeneration of gastrointestinal epithelium. In colorectal cancershowever, albeit the expression of IL-33 and the prevalence of mast cells are not necessarilyassociated, both appear to have a tumor-promoting role in most pre-clinical and human studies. Ingastric cancers, the authors discuss an interesting study involving an IL-33/mast cell/macrophageaxis that promotes tumor growth. Here, activation of mast cells by IL-33 resulted in the secretion ofmacrophage attracting factors and subsequent accumulation of pro-angiogenic and pro-tumorigenic macrophages in the gastric tumors. Finally, the authors discuss the possibility oforg November 2021 | Volume 12 | Article 8111251Schiavoni et al. Editorial: Type-2 Immunity in Cancerharnessing the IL-33/mast cell axis taking into account thedichotomous role they play in gastrointestinal tumors andother cancers.IL-33 is a pleiotropic cytokine that can activate both innateand adaptive immune cells (and stimulate both Th1 and Th2responses), which result in dichotomous roles in tumorimmunity, clearly depending on the tumor type and the natureof the TME. In another mini review article, Andreone et al. focuson the anti-tumoral mechanisms exerted by IL-33, viastimulation of several different immune effector cells. Recentliterature indicates that IL-33 can sustain the effector activity ofCD8+ T cells and NK cells and promote the functions of CD4+ Tlymphocytes in the TME. Moreover, IL-33 can activate thecytotoxic functions of eosinophils and basophils promotingtumor killing. In addition, IL-33/ST2 stimulation enhances theanti-tumor functions of ILC2 cells through multiplemechanisms, including recruitment of eosinophils and cross-presenting DCs, ultimately resulting in tumor cytotoxicity.Finally, recent evidence demonstrating that IL-33 canmodulate the expression of immune checkpoints (i.e., PD-1/PD-L1 and CTLA-4) in certain immune cells opens perspectivesfor targeting the IL-33/ST2 axis to increase immunotherapyefficacy. This is of specific interest as although immunecheckpoint inhibitors are one of the most promising avenuesin cancer immunotherapy only a subset of patients demonstratea clinical response. Therefore, it is critically important to identifypredictive biomarkers for a beneficial response to ICI therapyand to understand the role of all immune cells and solublemediators in cancer immunotherapy.Another epithelial-derived alarmin, TSLP, is a lymphopoietincommonly expressed in the skin, gut and lung tissues. Expressionof TSLP and/or its receptor is found in several human cancersand may be associated with the induction of a Type 2-proneTME. In a review article, Protti and De Monte debate Th2-dependent and Th2-independent roles of TSLP in several cancertypes and the possible therapeutic targeting of this cytokine.Several studies on human and mouse tumors found either pro-or anti-tumor activity of TSLP, mostly based on the associationbetween TSLP expression and the development of predominantTh2 inflammation in the tumor, or direct TSLP signaling ontumor cells. Protti and De Monte propose a model by whichTSLP released by tumor cells and cancer-associated fibroblastscan activate Type 2 immunity to foster cancer progression viamyeloid TSLP-expressing DCs and M2 macrophages in thestroma, which ultimately allow TSLP-DCs to activate Th2 pro-tumoral responses in the tissue draining lymph node. In view ofthe pro-tumor vs. antitumor function of TSLP in different tumortypes, its possible manipulation for therapeutic purposes willneed further investigation.Finally, in a detailed review, Marone et al. discuss thefunctional characteristics of mouse and human basophils, andhow these may dictate tumor fate. Basophils are a Type 2-associated cell subset whose role in cancer is only beginning tobe studied. They are a rare immune cell subset representing <1%of human peripheral blood leukocytes but they can accumulateFrontiers in Immunology | www.frontiersin.org 2in inflamed tissues and possess powerful effector mechanisms.Basophils can modulate cancer progression through theproduction of a plethora of angiogenic factors (e.g., VEGF-A,VEGF-B, HGF, ANGPT1 and CXCL8). Furthermore, basophilscan release DNA extracellular traps (ETs), which have anantibacterial function but may also promote metastasis andcancer-associated thrombosis, as described for neutrophil ETs.Basophils can also produce a variety of cytokines (e.g., IL-3, IL-4,IL-6 and IL-13) and display plasticity of phenotype and functionunder the influence of the TME. In addition, under appropriatestimulation, basophils can acquire tumoricidal propertiesin vitro. The generation of genetically engineered mousemodels has allowed studying the functional role of basophils inpancreatic ductal adenocarcinoma (PDAC) in vivo. Here, theauthors propose a model in which basophils recruited to thetumor-draining lymph nodes (TDLN) skew towards Th2 andM2 polarization through the production of IL-4 and by thismechanism play a relevant pro-tumorigenic role in PDACprogression. Overall, this review underlines that despite theestablished presence of basophils in human and experimentalcancers, further investigation is required to elucidate the role ofbasophils in tumor immunity.In sum, it is becoming increasingly clear that Type 2-associated cells and soluble mediators are an important part ofthe TME and can be central orchestrators of cancer development.The published articles in this Research Topic aim to provide abetter understanding of the mechanisms operated by Type 2immune effectors and their interplay with other components ofthe TME in specific tumor types. We hope this collection willinspire future work exploring and harnessing these overlookedimmune components for future therapeutic strategiesagainst cancer.AUTHOR CONTRIBUTIONSGS wrote the editorial and invited authors to contribute theResearch Topic. AM co-wrote the editorial and invited authors tocontribute to the Research Topic. JS co-wrote the editorial andinvited authors to contribute to the Research Topic. All authorscontributed to the article and approved the submitted version.FUNDINGGS is supported by AIRC (IG 21366). AM is supported by theUS-Israel Bi-national Science Foundation (grant no. 2015163),by the Israel Science Foundation (grants no. 886/15 and 542/20),the Israel Cancer Research Fund, the Richard Eimert ResearchFund on Solid Tumors (TAU), the Israel Cancer AssociationAvraham Rotstein Donation, the Cancer Biology ResearchCenter (TAU) and the Emerson Collective. JS is supported bythe Wellcome Trust (215488/Z/19/Z) and the British SkinFoundation (043/S/18).November 2021 | Volume 12 | Article 811125Schiavoni et al. Editorial: Type-2 Immunity in CancerREFERENCE1. Lloyd CM, Snelgrove RJ. Type 2 Immunity: Expanding Our View. Sci Immunol(2018) 3(25):eaat1604. doi: 10.1126/sciimmunol.aat1604Conflict of Interest: The authors declare that the research was conducted in theabsence of any commercial or financial relationships that could be construed as apotential conflict of interest.Publisher’s Note: All claims expressed in this article are solely those of the authorsand do not necessarily represent those of their affiliated organizations, or those ofFrontiers in Immunology | www.frontiersin.org 3the publisher, the editors and the reviewers. Any product that may be evaluated inthis article, or claim that may be made by its manufacturer, is not guaranteed orendorsed by the publisher.Copyright © 2021 Schiavoni, Munitz and Strid. This is an open-access articledistributed under the terms of the Creative Commons Attribution License(CC BY). The use, distribution or reproduction in other forums is permitted,provided the original author(s) and the copyright owner(s) are credited and thatthe original publication in this journal is cited, in accordance with acceptedacademic practice. No use, distribution or reproduction is permitted which doesnot comply with these terms.November 2021 | Volume 12 | Article 811125

Editorial: Emerging roles for type 2-associated cells and cytokines in cancer immunity

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Editorial: Emerging roles for type 2-associated cells and cytokines in cancer immunity

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