{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T16:11:07Z","timestamp":1783440667042,"version":"3.54.6"},"reference-count":46,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,11,3]],"date-time":"2023-11-03T00:00:00Z","timestamp":1698969600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Vet. Sci."],"abstract":"<jats:p>Cutaneous T-cell lymphoma (CTCL) is an uncommon type of lymphoma involving malignant skin-resident or skin-homing T cells. Canine epitheliotropic lymphoma (EL) is the most common form of CTCL in dogs, and it also spontaneously arises from T lymphocytes in the mucosa and skin. Clinically, it can be difficult to distinguish early-stage CTCLs apart from other forms of benign interface dermatitis (ID) in both dogs and people. Our objective was to identify novel biomarkers that can distinguish EL from other forms of ID, and perform comparative transcriptomics of human CTCL and canine EL. Here, we present a retrospective gene expression study that employed archival tissue from biorepositories. We analyzed a discovery cohort of 6 canines and a validation cohort of 8 canines with EL which occurred spontaneously in client-owned companion dogs. We performed comparative targeted transcriptomics studies using NanoString to assess 160 genes from lesional skin biopsies from the discovery cohort and 800 genes from the validation cohort to identify any significant differences that may reflect oncogenesis and immunopathogenesis. We further sought to determine if gene expression in EL and CTCL are conserved across humans and canines by comparing our data to previously published human datasets. Similar chemokine profiles were observed in dog EL and human CTCL, and analyses were performed to validate potential biomarkers and drivers of disease. In dogs, we found enrichment of T cell gene signatures, with upregulation of <jats:italic>IFNG<\/jats:italic>, <jats:italic>TNF<\/jats:italic>, <jats:italic>PRF1<\/jats:italic>, <jats:italic>IL15<\/jats:italic>, <jats:italic>CD244<\/jats:italic>, <jats:italic>CXCL10<\/jats:italic>, and <jats:italic>CCL5<\/jats:italic> in EL in dogs compared to healthy controls. Importantly, <jats:italic>CTSW<\/jats:italic>, <jats:italic>TRAT1<\/jats:italic> and <jats:italic>KLRK1<\/jats:italic> distinguished EL from all other forms of interface dermatitis we studied, providing much-needed biomarkers for the veterinary field. <jats:italic>XCL1<\/jats:italic>\/<jats:italic>XCL2<\/jats:italic> were also highly specific of EL in our validation cohort. Future studies exploring the oncogenesis of spontaneous lymphomas in companion animals will expand our understanding of these disorders. Biomarkers may be useful for predicting disease prognosis and treatment responses. We plan to use our data to inform future development of targeted therapies, as well as for repurposing drugs for both veterinary and human medicine.<\/jats:p>","DOI":"10.3389\/fvets.2023.1225764","type":"journal-article","created":{"date-parts":[[2023,11,3]],"date-time":"2023-11-03T09:08:47Z","timestamp":1699002527000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Cathepsin W, T-cell receptor-associated transmembrane adapter 1, lymphotactin and killer cell lectin like receptor K1 are sensitive and specific RNA biomarkers of canine epitheliotropic lymphoma"],"prefix":"10.3389","volume":"10","author":[{"given":"Jadesola Temitope","family":"Olayinka","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akanksha","family":"Nagarkar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana Junyue","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neil B.","family":"Wong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Romasco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cesar","family":"Piedra-Mora","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda","family":"Wrijil","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clement N.","family":"David","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather L.","family":"Gardner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas A.","family":"Robinson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelly L.","family":"Hughes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce","family":"Barton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheryl A.","family":"London","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ram\u00f3n M.","family":"Almela","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jillian M.","family":"Richmond","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,11,3]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"1703","DOI":"10.1182\/blood-2018-11-881268","article-title":"The 2018 update of the WHO-EORTC classification for primary cutaneous lymphomas","volume":"133","author":"Willemze","year":"2019","journal-title":"Blood"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"192","DOI":"10.1016\/j.ad.2016.08.009","article-title":"Clinicopathologic variants of mycosis fungoides","volume":"108","author":"Mu\u00f1oz-Gonz\u00e1lez","year":"2017","journal-title":"Actas Dermosifiliogr"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"854","DOI":"10.1001\/archderm.143.7.854","article-title":"Incidence of cutaneous T-cell lymphoma in the United States, 1973\u20132002","volume":"143","author":"Criscione","year":"2007","journal-title":"Arch Dermatol"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"563","DOI":"10.1177\/0300985815604724","article-title":"CD3 and CD20 coexpression in a case of canine cutaneous epitheliotropic T-cell lymphoma (mycosis fungoides)","volume":"53","author":"Brachelente","year":"2016","journal-title":"Vet Pathol"},{"key":"ref5","doi-asserted-by":"crossref","DOI":"10.1002\/9781119181200","volume-title":"Tumors in domestic animals.","author":"Meuten","year":"2016"},{"key":"ref6","doi-asserted-by":"crossref","DOI":"10.1002\/9780470752487","volume-title":"Skin diseases of the dog and cat: clinical and histopathologic diagnosis","author":"Gross","year":"2005"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1111\/j.1476-5829.2008.00176.x","article-title":"Canine cutaneous epitheliotropic T-cell lymphoma: a review","volume":"7","author":"Fontaine","year":"2009","journal-title":"Vet Comp Oncol"},{"key":"ref8","first-page":"421","article-title":"Canine cutaneous epitheliotropic lymphoma (mycosis fungoides) is a proliferative disorder of CD8+ T cells","volume":"144","author":"Moore","year":"1994","journal-title":"Am J Pathol"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1016\/j.cvsm.2018.08.007","article-title":"Canine and feline cutaneous epitheliotropic lymphoma and cutaneous lymphocytosis","volume":"49","author":"Rook","year":"2019","journal-title":"Vet Clin North Am Small Anim Pract"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"12","DOI":"10.3390\/genes12020160","article-title":"Transcriptional differences between canine cutaneous epitheliotropic lymphoma and immune-mediated dermatoses","volume":"12","author":"Gerber","year":"2021","journal-title":"Genes"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1016\/j.crimmu.2021.03.003","article-title":"Shared inflammatory and skin-specific gene signatures reveal common drivers of discoid lupus erythematosus in canines, humans and mice","volume":"2","author":"Garelli","year":"2021","journal-title":"Curr Res Immunol"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1186\/s40425-017-0215-8","article-title":"Gene expression markers of tumor infiltrating leukocytes","volume":"5","author":"Danaher","year":"2017","journal-title":"J Immunother Cancer"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1016\/j.jid.2020.04.026","article-title":"Diagnostic two-gene classifier in early-stage mycosis fungoides: a retrospective multicenter study","volume":"141","author":"Nielsen","year":"2021","journal-title":"J Invest Dermatol"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"488","DOI":"10.1186\/1471-2164-9-488","article-title":"BioVenn\u2014a web application for the comparison and visualization of biological lists using area-proportional Venn diagrams","volume":"9","author":"Hulsen","year":"2008","journal-title":"BMC Genomics"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"712","DOI":"10.1038\/nrc4027","article-title":"Cysteine cathepsin proteases: regulators of cancer progression and therapeutic response","volume":"15","author":"Olson","year":"2015","journal-title":"Nat Rev Cancer"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"674","DOI":"10.1016\/j.ccell.2020.03.016","article-title":"Cathepsin S regulates antigen processing and T cell activity in non-Hodgkin lymphoma","volume":"37","author":"Dheilly","year":"2020","journal-title":"Cancer Cell"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"107522","DOI":"10.1016\/j.celrep.2020.107522","article-title":"Cathepsin S alterations induce a tumor-promoting immune microenvironment in follicular lymphoma","volume":"31","author":"Bararia","year":"2020","journal-title":"Cell Rep"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1016\/S0014-5793(97)00118-X","article-title":"Human cathepsin W, a putative cysteine protease predominantly expressed in CD8+ T-lymphocytes","volume":"405","author":"Linnevers","year":"1997","journal-title":"FEBS Lett"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"2172","DOI":"10.4049\/jimmunol.167.4.2172","article-title":"Human cathepsin W, a cysteine protease predominantly expressed in NK cells, is mainly localized in the endoplasmic reticulum","volume":"167","author":"Wex","year":"2001","journal-title":"J Immunol"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"266","DOI":"10.1016\/j.exphem.2008.10.011","article-title":"Cathepsin W expressed exclusively in CD8+ T cells and NK cells, is secreted during target cell killing but is not essential for cytotoxicity in human CTLs","volume":"37","author":"Stoeckle","year":"2009","journal-title":"Exp Hematol"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"3015","DOI":"10.1182\/blood-2006-12-061507","article-title":"Lesional gene expression profiling in cutaneous T-cell lymphoma reveals natural clusters associated with disease outcome","volume":"110","author":"Shin","year":"2007","journal-title":"Blood"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"491","DOI":"10.1016\/j.prp.2008.04.010","article-title":"The cathepsin family and their role in colorectal cancer","volume":"204","author":"Kuester","year":"2008","journal-title":"Pathol Res Pract"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"1269","DOI":"10.1084\/jem.193.11.1269","article-title":"The transmembrane adaptor protein TRIM regulates T cell receptor (TCR) expression and TCR-mediated signaling via an association with the TCR zeta chain","volume":"193","author":"Kirchgessner","year":"2001","journal-title":"J Exp Med"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"807","DOI":"10.1016\/j.immuni.2006.08.024","article-title":"T cell receptor-interacting molecule acts as a chaperone to modulate surface expression of the CTLA-4 coreceptor","volume":"25","author":"Valk","year":"2006","journal-title":"Immunity"},{"key":"ref25","first-page":"201","article-title":"Lack of association between an exon 1 CTLA-4 gene polymorphism A (49) G and multiple sclerosis in a polish population of the lower Silesia region","volume":"51","author":"Bo\u0107ko","year":"2003","journal-title":"Arch Immunol Ther Exp"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"575","DOI":"10.1158\/2326-6066.CIR-15-0098","article-title":"NKG2D receptor and its ligands in host defense","volume":"3","author":"Lanier","year":"2015","journal-title":"Cancer Immunol Res"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"1026","DOI":"10.1182\/blood-2009-06-227579","article-title":"Molecular signatures to improve diagnosis in peripheral T-cell lymphoma and prognostication in angioimmunoblastic T-cell lymphoma","volume":"115","author":"Iqbal","year":"2010","journal-title":"Blood"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1172\/jci.insight.124233","article-title":"Benign T cells drive clinical skin inflammation in cutaneous T cell lymphoma","volume":"4","author":"Vieyra-Garcia","year":"2019","journal-title":"JCI Insight"},{"key":"ref29","doi-asserted-by":"publisher","first-page":"1593","DOI":"10.1016\/S0002-9440(10)64114-4","article-title":"Differential expression of cytotoxic molecules and killer cell inhibitory receptors in CD8+ and CD56+ cutaneous lymphomas","volume":"158","author":"Kamarashev","year":"2001","journal-title":"Am J Pathol"},{"key":"ref30","doi-asserted-by":"publisher","first-page":"448","DOI":"10.1189\/jlb.0103024","article-title":"Many chemokines including CCL20\/MIP-3\u03b1 display antimicrobial activity","volume":"74","author":"Yang","year":"2003","journal-title":"J Leukoc Biol"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"4812","DOI":"10.1158\/1078-0432.CCR-06-0532","article-title":"Th1 response and cytotoxicity genes are down-regulated in cutaneous T-cell lymphoma","volume":"12","author":"Hahtola","year":"2006","journal-title":"Clin Cancer Res"},{"key":"ref32","doi-asserted-by":"publisher","first-page":"124","DOI":"10.1186\/s12943-021-01419-2","article-title":"Single-cell RNA sequencing reveals markers of disease progression in primary cutaneous T-cell lymphoma","volume":"20","author":"Rindler","year":"2021","journal-title":"Mol Cancer"},{"key":"ref33","doi-asserted-by":"publisher","first-page":"1013","DOI":"10.1111\/bjd.20512","article-title":"Single-cell RNA sequencing profiling in a patient with discordant primary cutaneous B-cell and T-cell lymphoma reveals micromilieu-driven immune skewing","volume":"185","author":"Jonak","year":"2021","journal-title":"Br J Dermatol"},{"key":"ref34","doi-asserted-by":"publisher","first-page":"1421","DOI":"10.1080\/10428190600581807","article-title":"A lymphotactin-producing monoclonal T-cell lymphoproliferative disorder with extreme lymphocytopenia and progressive leukoencephalopathy","volume":"47","author":"Visentini","year":"2006","journal-title":"Leuk Lymphoma"},{"key":"ref35","doi-asserted-by":"publisher","first-page":"57","DOI":"10.4049\/jimmunol.167.1.57","article-title":"Lymphotactin expression by engineered myeloma cells drives tumor regression: mediation by CD4+ and CD8+ T cells and neutrophils expressing XCR1 receptor","volume":"167","author":"Cairns","year":"2001","journal-title":"J Immunol"},{"key":"ref36","doi-asserted-by":"publisher","first-page":"1185","DOI":"10.1038\/s41416-020-0757-2","article-title":"Anticancer effects of chemokine-directed antigen delivery to a cross-presenting dendritic cell subset with immune checkpoint blockade","volume":"122","author":"Mizumoto","year":"2020","journal-title":"Br J Cancer"},{"key":"ref37","doi-asserted-by":"publisher","first-page":"20","DOI":"10.21037\/cco.2019.01.02","article-title":"Systemic therapy of cutaneous T-cell lymphoma (CTCL)","volume":"8","author":"Alpdogan","year":"2019","journal-title":"Chin Clin Oncol"},{"key":"ref38","doi-asserted-by":"publisher","first-page":"483","DOI":"10.1016\/S0002-9440(10)65144-9","article-title":"Primary cutaneous CD8-positive epidermotropic cytotoxic T cell lymphomas. A distinct clinicopathological entity with an aggressive clinical behavior","volume":"155","author":"Berti","year":"1999","journal-title":"Am J Pathol"},{"key":"ref39","doi-asserted-by":"publisher","first-page":"513","DOI":"10.1016\/j.molonc.2012.12.006","article-title":"VGLL3 expression is associated with a tumor suppressor phenotype in epithelial ovarian cancer","volume":"7","author":"Gambaro","year":"2013","journal-title":"Mol Oncol"},{"key":"ref40","doi-asserted-by":"publisher","first-page":"1077","DOI":"10.1002\/mc.20535","article-title":"Characterization of the 3p12.3-pcen region associated with tumor suppression in a novel ovarian cancer cell line model genetically modified by chromosome 3 fragment transfer","volume":"48","author":"Cody","year":"2009","journal-title":"Mol Carcinog"},{"key":"ref41","doi-asserted-by":"publisher","first-page":"1355","DOI":"10.1038\/s41598-020-58493-7","article-title":"VGLL3 is a prognostic biomarker and correlated with clinical pathologic features and immune infiltrates in stomach adenocarcinoma","volume":"10","author":"Zhang","year":"2020","journal-title":"Sci Rep"},{"key":"ref42","doi-asserted-by":"publisher","first-page":"8798","DOI":"10.1074\/jbc.RA120.012781","article-title":"Vestigial-like family member 3 (VGLL3), a cofactor for TEAD transcription factors, promotes cancer cell proliferation by activating the Hippo pathway","volume":"295","author":"Hori","year":"2020","journal-title":"J Biol Chem"},{"key":"ref43","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1007\/s10875-010-9464-8","article-title":"Interleukin-16 as a marker of Sezary syndrome onset and stage","volume":"31","author":"Richmond","year":"2011","journal-title":"J Clin Immunol"},{"key":"ref44","doi-asserted-by":"publisher","first-page":"1581","DOI":"10.1007\/s00432-011-1017-x","article-title":"Introduction of pro-interleukin-16 inhibits T-lymphoblastic leukemia growth in mice","volume":"137","author":"Richmond","year":"2011","journal-title":"J Cancer Res Clin Oncol"},{"key":"ref45","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1016\/S0268-960X(03)00004-3","article-title":"Primary cutaneous lymphomas: a review with current treatment options","volume":"17","author":"Querfeld","year":"2003","journal-title":"Blood Rev"},{"key":"ref46","doi-asserted-by":"publisher","first-page":"300","DOI":"10.1016\/j.jaad.2009.02.035","article-title":"Primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma","volume":"62","author":"Gormley","year":"2010","journal-title":"J Am Acad Dermatol"}],"container-title":["Frontiers in Veterinary Science"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fvets.2023.1225764\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,3]],"date-time":"2023-11-03T09:08:53Z","timestamp":1699002533000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fvets.2023.1225764\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,11,3]]},"references-count":46,"alternative-id":["10.3389\/fvets.2023.1225764"],"URL":"https:\/\/doi.org\/10.3389\/fvets.2023.1225764","relation":{},"ISSN":["2297-1769"],"issn-type":[{"value":"2297-1769","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,11,3]]},"article-number":"1225764"}}