{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T01:01:41Z","timestamp":1783040501226,"version":"3.54.6"},"reference-count":46,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,1,9]],"date-time":"2023-01-09T00:00:00Z","timestamp":1673222400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001807","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de S\u00e3o Paulo","doi-asserted-by":"publisher","award":["2020\/16736-0"],"award-info":[{"award-number":["2020\/16736-0"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003593","name":"Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["5R01CA246368-02"],"award-info":[{"award-number":["5R01CA246368-02"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002322","name":"Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002322","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>The COVID-19 pandemic, caused by the coronavirus SARS-CoV-2, has impacted health across all sectors of society. A cytokine-release syndrome, combined with an inefficient response of innate immune cells to directly combat the virus, characterizes the severe form of COVID-19. While immune factors involved in the development of severe COVID-19 in the general population are becoming clearer, identification of the immune mechanisms behind severe disease in oncologic patients remains uncertain.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Here we evaluated the systemic immune response through the analysis of soluble blood immune factors and anti-SARS-CoV-2 antibodies within the early days of a positive SARS-CoV-2 diagnostic in oncologic patients.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Individuals with hematologic malignancies that went on to die from COVID-19 displayed at diagnosis severe leukopenia, low antibody production against SARS-CoV-2 proteins, and elevated production of innate immune cell recruitment and activation factors. These patients also displayed correlation networks in which IL-2, IL-13, TNF-alpha, IFN-gamma, and FGF2 were the focal points. Hematologic cancer patients that showed highly networked and coordinated anti-SARS-CoV-2 antibody production, with central importance of IL-4, IL-5, IL-12A, IL-15, and IL-17A, presented only mild COVID-19. Conversely, solid tumor patients that had elevated levels of inflammatory cytokines IL-6, CXCL8, and lost the coordinate production of anti-virus antibodies developed severe COVID-19 and died. Patients that displayed positive correlation networks between anti-virus antibodies, and a regulatory axis involving IL-10 and inflammatory cytokines recovered from the disease. We also provided evidence that CXCL8 is a strong predictor of death for oncologic patients and could be an indicator of poor prognosis within days of the positive diagnostic of SARS-CoV-2 infection.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Our findings defined distinct systemic immune profiles associated with COVID-19 clinical outcome of patients with cancer and COVID-19. These systemic immune networks shed light on potential immune mechanisms involved in disease outcome, as well as identify potential clinically useful biomarkers.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2022.1052104","type":"journal-article","created":{"date-parts":[[2023,1,9]],"date-time":"2023-01-09T11:23:23Z","timestamp":1673263403000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Distinct systemic immune networks define severe vs. mild COVID-19 in hematologic and solid cancer patients"],"prefix":"10.3389","volume":"13","author":[{"given":"Fl\u00e1vio","family":"Pignataro-Oshiro","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda B.","family":"Figueiredo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nayane A. L.","family":"Galdino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katia L. P.","family":"Morais","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walderez O.","family":"Dutra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bianca Grassi de Miranda","family":"Silva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diego","family":"Feriani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fl\u00e1via de Azevedo","family":"Abrantes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivan Leonardo Avelino Fran\u00e7a e","family":"Silva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jayr Schmidt","family":"Filho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juliana Val\u00e9ria de Souza","family":"Framil","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcelle Goldner","family":"Cesca","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel Sim\u00f5es Pimenta","family":"Riechelmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marjorie V.","family":"Batista","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth J.","family":"Gollob","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,1,9]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/s41579-020-00459-7","article-title":"Characteristics of SARS-CoV-2 and COVID-19","volume":"19","author":"Hu","year":"2020","journal-title":"Nat Rev Microbiol"},{"key":"B2","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1128\/CMR.00028-20","article-title":"Coronavirus disease 2019 - COVID19","volume":"33","author":"Dhama","year":"2020","journal-title":"Clin Microbiol Rev"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1038\/s41562-020-0928-4","article-title":"Epidemiological and clinical characteristics of the COVID-19 epidemic in Brazil","volume":"4","author":"De Souza","year":"2020","journal-title":"Nat Hum Behav [Internet]"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.lana.2021.100107","article-title":"First and second COVID-19 waves in Brazil: A cross-sectional study of patients\u2019 characteristics related to hospitalization and in-hospital mortality","author":"Zeiser","year":"2022","journal-title":"Lancet Reg Heal - Am"},{"key":"B5","unstructured":"Brazilian Ministry of health - DATASUS. painel coronav\u00edrus [Internet]2022"},{"key":"B6","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1590\/0037-8682-0167-2020","article-title":"Covid-19 in Brazil: Advantages of a socialized unified health system and preparation to contain cases","volume":"53","author":"Croda","year":"2020","journal-title":"Rev Soc Bras Med Trop"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-020-0331-4","article-title":"Pathological inflammation in patients with COVID-19: a key role for monocytes and macrophages","volume":"20","author":"Merad","year":"2020","journal-title":"Nat Rev Immunol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(20)30442-3","article-title":"COVID-19 prevalence and mortality in patients with cancer and the effect of primary tumour subtype and patient demographics: a prospective cohort study","volume":"21","author":"Lee","year":"2020","journal-title":"Lancet Oncol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-020-0979-0","article-title":"Determinants of COVID-19 disease severity in patients with cancer","volume":"26","author":"Robilotti","year":"2020","journal-title":"Nat Med [Internet]"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1038\/s43018-020-00122-3","article-title":"The immuno-oncological challenge of COVID-19","volume":"1","author":"Derosa","year":"2020","journal-title":"Nat Cancer"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciaa1079","article-title":"Are all patients with cancer at heightened risk for severe coronavirus disease 2019 (COVID-19)","volume":"72","author":"Chamilos","year":"2020","journal-title":"Clin Infect Dis"},{"key":"B12","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1038\/s41591-020-01202-8","article-title":"Immune determinants of COVID-19 disease presentation and severity","volume":"27","author":"Brodin","year":"2021","journal-title":"Nat Med [Internet]."},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1053\/j.seminoncol.2021.01.003","article-title":"Differences in mortality of cancer patients with COVID-19 in a Brazilian cancer center","volume":"48","author":"Fernandes","year":"2021","journal-title":"Semin Oncol [Internet]."},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(20)30628-0","article-title":"COVID-19: consider cytokine storm syndromes and immunosuppression","volume":"395","author":"Mehta","year":"2020","journal-title":"Lancet [Internet]."},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1590\/1806-9282.66.8.1152","article-title":"Laboratory findings in SARS-CoV-2 infections: State of the art","volume":"66","author":"Pereira","year":"2020","journal-title":"Rev Assoc Med Bras"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.25829","article-title":"Hematological findings and complications of COVID-19","volume":"95","author":"Terpos","year":"2020","journal-title":"Am J Hematol"},{"key":"B17","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1016\/j.ccell.2021.01.001","article-title":"Acute immune signatures and their legacies in severe acute respiratory syndrome coronavirus-2 infected cancer patients","volume":"39","author":"Abdul-Jawad","year":"2021","journal-title":"Cancer Cell"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2588-y","article-title":"Longitudinal analyses reveal immunological misfiring in severe COVID-19","volume":"584","author":"Lucas","year":"2020","journal-title":"Nature."},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.7150\/thno.15625","article-title":"Role of the CXCL8-CXCR1\/2 axis in cancer and inflammatory diseases","volume":"7","author":"Ha","year":"2017","journal-title":"Theranostics."},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1084\/jem.180.4.1395","article-title":"Interleukin (IL) 15 is a novel cytokine that activates human natural killer cells via components of the IL-2 receptor","volume":"180","author":"Carson","year":"1994","journal-title":"J Exp Med"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1038\/s41584-020-0451-z","article-title":"COVID-19 revisiting inflammatory pathways of arthritis","volume":"16","author":"Schett","year":"2020","journal-title":"Nat Rev Rheumatol [Internet]"},{"key":"B22","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1111\/imr.12621","article-title":"Overview of the IL-1 family in innate inflammation and acquired immunity","volume":"281","author":"Dinarello","year":"2018","journal-title":"Immunol Rev"},{"key":"B23","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1684\/ecn.2009.0155","article-title":"Inflammatory cells and chemokines sustain FGF2-induced angiogenesis","volume":"20","author":"Presta","year":"2009","journal-title":"Eur Cytokine Netw"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.01626","article-title":"Overview: Systemic inflammatory response derived from lung injury caused by SARS-CoV-2 infection explains severe outcomes in","volume":"11","author":"Polidoro","year":"2020","journal-title":"Front Immunol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-020-0602-4","article-title":"COVID-19 severity correlates with airway epithelium\u2013immune cell interactions identified by single-cell analysis","volume":"38","author":"Chua","year":"2020","journal-title":"Nat Biotechnol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-021-01386-7","article-title":"CD8+ T cells contribute to survival in patients with COVID-19 and hematologic cancer","volume":"27","author":"Bange","year":"2021","journal-title":"Nat Med [Internet]."},{"key":"B27","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1126\/sciimmunol.abe0240","article-title":"Defining the features and duration of antibody responses to SARS-CoV-2 infection associated with disease severity and outcome","volume":"5","author":"R\u00f6ltgen","year":"2021","journal-title":"Sci Immunol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1101\/2021.01.04.21249236","article-title":"Saliva viral load is a dynamic unifying correlate of COVID-19 severity and mortality","author":"Silva","year":"2021","journal-title":"medRxiv"},{"key":"B29","doi-asserted-by":"publisher","first-page":"20","DOI":"10.3390\/biom5010020","article-title":"Factors regulating immunoglobulin production by normal and disease-associated plasma cells","volume":"5","author":"Jackson","year":"2015","journal-title":"Biomolecules."},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.00827","article-title":"Reduction and functional exhaustion of T cells in patients with coronavirus disease 2019 (COVID-19)","volume":"11","author":"Diao","year":"2020","journal-title":"Front Immunol"},{"key":"B31","doi-asserted-by":"publisher","first-page":"1489","DOI":"10.1016\/j.cell.2020.05.015","article-title":"Targets of T cell responses to SARS-CoV-2 coronavirus in humans with COVID-19 disease and unexposed individuals","volume":"181","author":"Grifoni","year":"2020","journal-title":"Cell [Internet]."},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1080\/21505594.2016.1208866","article-title":"Immune reconstitution post allogeneic transplant and the impact of immune recovery on the risk of infection","volume":"7","author":"Mehta","year":"2016","journal-title":"Virulence [Internet]."},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1002\/onco.13828","article-title":"Humoral immune response of SARS-CoV-2\u2013infected patients with cancer: Influencing factors and mechanisms","volume":"26","author":"Esperan\u00e7a-Martins","year":"2021","journal-title":"Oncologist [Internet]."},{"key":"B34","doi-asserted-by":"publisher","first-page":"1081","DOI":"10.1016\/j.ccell.2021.06.002","article-title":"Seroconversion rates following COVID-19 vaccination among patients with cancer","volume":"39","author":"Thakkar","year":"2021","journal-title":"Cancer Cell [Internet]."},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1101\/2020.04.19.20068015","article-title":"Impaired type I interferon activity and exacerbated inflammatory responses in severe covid-19 patients","volume":"369","author":"Hadjadj","year":"2020","journal-title":"Scient"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1038\/d41586-020-03070-1","article-title":"Interferon deficiency can lead to severe COVID","volume":"587","author":"Meffre","year":"2020","journal-title":"Nature."},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.R400025200","article-title":"Samols d","volume":"279","author":"Black","year":"2004","journal-title":"C-reactive protein. J Biol Chem [Internet]."},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1007\/s00281-017-0629-x","article-title":"Pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology","volume":"39","author":"Channappanavar","year":"2017","journal-title":"Semin Immunopathol"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1003049","article-title":"A brief history of IL-9","volume":"186","author":"Goswami","year":"2022","journal-title":"J Immunol"},{"key":"B40","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1186\/s12964-020-00538-5","article-title":"IL-9 and IL-9-producing cells in tumor immunity","volume":"18","author":"Wan","year":"2020","journal-title":"Cell Communication and Signaling"},{"key":"B41","doi-asserted-by":"publisher","first-page":"1475","DOI":"10.1016\/j.cell.2020.05.006","article-title":"Host-viral infection maps reveal signatures of severe COVID-19 patients","volume":"181","author":"Bost","year":"2020","journal-title":"Cell [Internet]."},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-03148-w","article-title":"Circuits between infected macrophages and T cells in SARS-CoV-2 pneumonia","volume":"590","author":"Grant","year":"2021","journal-title":"Nature"},{"key":"B43","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s13054-020-03079-y","article-title":"VEGF-d: A novel biomarker for detection of COVID-19 progression","volume":"24","author":"Kong","year":"2020","journal-title":"Crit Care"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(20)30483-7","article-title":"A minimal common outcome measure set for COVID-19 clinical research","volume":"20","author":"Marshall","year":"2020","journal-title":"Lancet Infect Dis"},{"key":"B45","doi-asserted-by":"publisher","first-page":"693","DOI":"10.1056\/NEJMoa2021436","article-title":"The RECOVERY collaborative group. dexamethasone in hospitalized patients with covid-19","volume":"384","author":"Metsalu","year":"2021","journal-title":"N Engl J Med"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv468","article-title":"ClustVis: A web tool for visualizing clustering of multivariate data using principal component analysis and heatmap","volume":"43","author":"Metsalu","year":"2015","journal-title":"Nucleic Acids Res"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.1052104\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,9]],"date-time":"2023-01-09T11:23:28Z","timestamp":1673263408000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.1052104\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,9]]},"references-count":46,"alternative-id":["10.3389\/fimmu.2022.1052104"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2022.1052104","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,1,9]]},"article-number":"1052104"}}