Barrett, Lucy W.

Gray, Elin S.

Waithman, Jason

Wells, James W.

English

Research Online @ ECU

Edith Cowan University Research Online ECU Publications Post 2013 2019 Editorial: Insights into biomarkers, cytokines, and chemokines in skin cancer Lucy W. Barrett Elin S. Gray Edith Cowan University, e.gray@ecu.edu.au James W. Wells Jason Waithman Follow this and additional works at: https://ro.ecu.edu.au/ecuworkspost2013  Part of the Medicine and Health Sciences Commons 10.3389/fmed.2019.00199 Barrett, L. W., Gray, E. S., Wells, J. W., & Waithman, J. (2019). Editorial: Insights into biomarkers, cytokines, and chemokines in skin cancer. Frontiers in Medicine, 6. Available here. This Editorial is posted at Research Online. https://ro.ecu.edu.au/ecuworkspost2013/7139 EDITORIALpublished: 25 September 2019doi: 10.3389/fmed.2019.00199Frontiers in Medicine | www.frontiersin.org 1 September 2019 | Volume 6 | Article 199Edited and reviewed by:Robert Gniadecki,University of Alberta, Canada*Correspondence:Lucy W. Barrettlucy.barrett@telethonkids.org.auSpecialty section:This article was submitted toDermatology,a section of the journalFrontiers in MedicineReceived: 01 August 2019Accepted: 27 August 2019Published: 25 September 2019Citation:Barrett LW, Gray ES, Wells JW andWaithman J (2019) Editorial: InsightsInto Biomarkers, Cytokines, andChemokines in Skin Cancer.Front. Med. 6:199.doi: 10.3389/fmed.2019.00199Editorial: Insights Into Biomarkers,Cytokines, and Chemokines in SkinCancerLucy W. Barrett 1,2*, Elin S. Gray 3, James W. Wells 4,5 and Jason Waithman 11 Telethon Kids Institute, Perth Children’s Hospital, University of Western Australia, Nedlands, WA, Australia, 2 Institute forRespiratory Health, Sir Charles Gairdner Hospital, Nedlands, WA, Australia, 3 School of Medical and Health Sciences, EdithCowan University, Joondalup, WA, Australia, 4 The University of Queensland Diamantina Institute, The University ofQueensland, Woolloongabba, QLD, Australia, 5Dermatology Research Centre, The University of Queensland,Woolloongabba, QLD, AustraliaKeywords: skin cancer, immunology, biomarkers, chemokines, cytokines, immunotherapy, skin, lymphocytetraffickingEditorial on the Research TopicInsights Into Biomarkers, Cytokines, and Chemokines in Skin CancerAs our understanding of immune system involvement in skin cancer has increased, so has thedevelopment of immunotherapies to target aggressive, un-resectable, or metastatic skin cancers,resulting in significant improvements in survival for previously untreatable patients. However,the high rate of non-responders and the development of resistance to immunotherapy over timehighlights the need to improve the efficacy of these treatments. The skin microenvironmentis unlike other non-lymphoid organs in so far as lymphocytes constantly traffic to and fromthe skin and immune surveillance occurs even in the absence of infection (Lafouresse andGroom). Thus, the immune system plays a critical role in the maintenance of a healthy skinmicroenvironment, and disruption of immune surveillance mechanisms is thought to contribute tomultiple skin neoplasia’s, including cancer. Our current Research Topic highlights the complexityof the relationship between the skin, immune system and skin cancer, and underlines the needto characterize the specific molecular mechanisms involved in cell trafficking in a context-specificmanner. Here we provide a brief overview of the five review articles and two original researchpapers that contributed to our recent Research Topic, focusing on general ideas that have emergedand implications for future research in the field.Amajor theme running through this topic is the dissection ofmolecularmechanisms involved inlymphocyte trafficking into the skin and tumors, with a particular focus on the specific chemokinesinvolved (Lafouresse and Groom; Yam and Chtanova; Kuo et al.). Trafficking of immune cellsinto the skin is a complex and highly regulated process as each cell type responds to a specificset of signals, and chemokines and their receptors can be variably expressed by both normalskin cells and malignant cells. In the review by Kuo et al., the role of the chemokine receptorCXCR3 and associated ligands in interferon-induced inflammatory responses and skin canceris examined in detail, and describes how CXCR3 expression on immune cells often promotesanti-tumor responses, while conversely, expression on tumor cells can lead to metastasis. Evidencefor the opposing roles of immune cells in cancer progression and metastasis is further describedin the mini review by Yam and Chtanova, in which the roles of other chemokine receptors andligands in the trafficking of dendritic cells, macrophages, neutrophils and natural killer cells intotumors is examined. In addition to the movement of lymphocytes, Ju et al. further address thepathways involved in metastasic spread, with chemokines and their receptors remaining a keyBarrett et al. Biomarkers and Cytokines in Skin Cancerfocus. Importantly, the authors discuss the concept that themechanisms behind metastatic spread may also enhance tumorcell survival, making these pathways attractive targets forfuture therapies.Tumors that are rich in cytotoxic T cells tend to be associatedwith a better prognosis and response to immunotherapy(Lafouresse and Groom; Yam and Chtanova). However, the roleof innate immune cells including dendritic cells, macrophages,neutrophils, and natural killer cells in tumors is more complex, asthey can mediate anti-tumor responses through the recruitmentof cytotoxic T cells, or alternatively may inhibit anti-tumorresponses through expression of suppressive factors, resultingin enhanced tumor growth (Yam and Chtanova). Even when Tcells are effectively recruited to tumors, they may be inhibitedby exhaustion or infiltration of suppressive T regulatory cells(Lafouresse and Groom). A greater understanding of theinterplay between innate and adaptive lymphocytes, and how thisultimately influences cancer growth, is needed to promote greaterresponse rates to immunotherapy, which is the second majortheme of our Research Topic. The articles presented emphasizethe urgent need to understand the specific mechanisms behindnon-response or developed resistance to emerging treatments.To improve responses and treatment regimes, biomarkersand new predictors for treatment response are urgently needed(Bridge et al.). In their review, Bridge et al. examinedcurrent research into checkpoint inhibitor therapy for variousskin cancers and the advances that have been made inidentifying biomarkers for non-response, tolerance, and toxicity.The authors discuss the current state of immunotherapy formetastatic skin cancers, the limitations of the current biomarkers,and address important questions pertaining to the generalunpredictability of the responses to checkpoint inhibitor (CPI)therapies, such as: Can CPIs be re-administered in the case ofrelapse? Do all CPI treatments work through the same pathways,meaning patients who are resistant to one would be resistantto others? And when should treatment be stopped? Thesequestions reflect some of the current priorities for improvingimmunotherapy outcomes.T cell exhaustion, whereby T cells progressively lose theireffector function, presents a major challenge to effectiveimmunotherapies. An original study by Graves et al. analyzed theexpression of inhibitory markers on the surface of T cells from16 patients treated with Pembrolizumab, an anti-PD-1 therapyfor metastatic melanoma. They identified upregulation of PD-1and TIM-3 on CD8T cells as potential biomarkers to identifynon-responders to Pembrolizumab therapy. The second originalresearch paper presented as part of this topic also details a searchfor biomarkers, this time for squamous cell carcinoma (SCC).Crawford et al. identified two anthrax toxin receptors, TumorEndothelial Marker 8 (TEM8) and Capillary MorphogenesisGene 2 (CMG2), that are upregulated on SCC cells. Protectiveantigen (PA), a protein from Bacillus anthracis that has beenshown to bind to these receptors, was fluorescently labeled andintravenously infused in a mouse model of SCC. The authorsshowed that they were able to detect tumor-specific uptakeof PA through binding with TEM8. This research identifyingTEM8 as a potential biomarker for SCC has importantimplications for treatment, as it could facilitate early, accuratedetection of skin malignancy and enhance surgical precision oftumor removal.The studies in this issue illustrate the complexities andchallenges researchers face in designing effective and long-lastingimmunotherapies for skin cancer. Through detailed studies,such as those presented here, it may well become possible toharness the immune system to destroy skin cancer and preventits recurrence. Characterization of immune cell movements andfunctions within the skin and in response to immunotherapiesare a priority in order to provide the best possible treatment forpatients in the future.AUTHOR CONTRIBUTIONSLB prepared the initial manuscript. EG, JWW, and JW allprovided feedback and edited the final manuscript.Conflict of Interest Statement: The authors declare that the research wasconducted in the absence of any commercial or financial relationships that couldbe construed as a potential conflict of interest.Copyright © 2019 Barrett, Gray, Wells andWaithman. 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 theoriginal author(s) and the copyright owner(s) are credited and that the originalpublication in this journal is cited, in accordance with accepted academic practice.No use, distribution or reproduction is permitted which does not comply with theseterms.Frontiers in Medicine | www.frontiersin.org 2 September 2019 | Volume 6 | Article 199

Editorial: Insights into biomarkers, cytokines, and chemokines in skin cancer

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Editorial: Insights into biomarkers, cytokines, and chemokines in skin cancer

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