{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,4]],"date-time":"2026-02-04T19:14:50Z","timestamp":1770232490452,"version":"3.49.0"},"reference-count":28,"publisher":"Springer Science and Business Media LLC","issue":"6","license":[{"start":{"date-parts":[[2024,9,11]],"date-time":"2024-09-11T00:00:00Z","timestamp":1726012800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,9,11]],"date-time":"2024-09-11T00:00:00Z","timestamp":1726012800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"NIH Fogarty International Center training grant","award":["1D43-TW010345"],"award-info":[{"award-number":["1D43-TW010345"]}]},{"name":"NHLS Research Trust","award":["947911"],"award-info":[{"award-number":["947911"]}]},{"name":"University of the Witwatersrand"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Immunol Res"],"published-print":{"date-parts":[[2024,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Diffuse large B-cell lymphoma (DLBCL) is a common malignancy among people living with HIV. Macrophage enrichment of the tumour microenvironment (TME) is a prognostic factor in DLBCL among immunocompetent people, with some studies reporting that macrophage enrichment predicts a superior response to rituximab therapy. The macrophage phenotype is also important, with reportedly poorer outcomes with enrichment of anti-inflammatory (M2) macrophages. To date, the relationship between the type\/number of tumour macrophages and outcomes in HIV-associated DLBCL (HIV-DLBCL) has been poorly explored. In this study, we assessed tumour macrophage numbers in a South African cohort of patients with DLBCL and a high HIV-seropositivity rate. Immunohistochemistry for CD68 and CD163 was performed on the diagnostic biopsies of 79 patients with DLBCL. Relevant information was documented from the clinical records, including disease stage, international-prognostic index score, HIV-related parameters, C-reactive protein, ferritin levels and immune cell numbers (monocytes, lymphocytes and neutrophils). Survival analysis was performed using Kaplan\u2013Meier survival estimates, and the correlation between tumour macrophage numbers and a variety of immunological parameters was assessed using Spearman\u2019s rho. Of the 79 patients included, 87.2% were living with HIV, and rituximab therapy was used in 46.9%. Tumour macrophage numbers were not related to HIV status, but low pro-inflammatory (M1) macrophage numbers (CD68\u2009+\u2009CD163\u2009\u2212) were significantly associated with poorer outcomes (HR 2.02, <jats:italic>p<\/jats:italic>\u2009=\u20090.03). M2 macrophage (CD68\u2009+\u2009CD163\u2009+) enrichment was not predictive of survival but was associated with improved response to rituximab therapy (HR 0.19; <jats:italic>p<\/jats:italic>\u2009=\u20090.002). Macrophage numbers were marginally correlated with ferritin levels, which showed modest performance as a peripheral blood biomarker of the TME macrophage status (AUC 0.6 at a level of 374\u00a0\u00b5g\/L), and high ferritin levels were associated with a superior response to rituximab-therapy (HR 0.28, <jats:italic>p<\/jats:italic>\u2009=\u20090.034). Pro-inflammatory macrophages are important in tumour control in HIV-DLBCL, while M2 macrophage enrichment improves the response to rituximab therapy. Ferritin shows promise as a biomarker for identifying patients more likely to benefit from rituximab therapy.<\/jats:p>","DOI":"10.1007\/s12026-024-09537-x","type":"journal-article","created":{"date-parts":[[2024,9,11]],"date-time":"2024-09-11T09:03:21Z","timestamp":1726045401000},"page":"1393-1403","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Tumour-associated macrophages in diffuse large B-cell lymphoma: the prognostic and therapeutic impact in a South African centre with high HIV seroprevalence"],"prefix":"10.1007","volume":"72","author":[{"given":"Jenifer","family":"Vaughan","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tracey","family":"Wiggill","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zainab","family":"Mia","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Moosa","family":"Patel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2024,9,11]]},"reference":[{"issue":"22","key":"9537_CR1","doi-asserted-by":"publisher","first-page":"2313","DOI":"10.1056\/NEJMoa0802885","volume":"359","author":"G Lenz","year":"2008","unstructured":"Lenz G, et al. Stromal gene signatures in large-B-cell lymphomas. N Engl J Med. 2008;359(22):2313\u201323. https:\/\/doi.org\/10.1056\/NEJMoa0802885.","journal-title":"N Engl J Med"},{"issue":"2","key":"9537_CR2","doi-asserted-by":"publisher","first-page":"110","DOI":"10.1002\/hon.2142","volume":"33","author":"F Marchesi","year":"2015","unstructured":"Marchesi F, et al. High density of CD68+\/CD163+ tumour-associated macrophages (M2-TAM) at diagnosis is significantly correlated to unfavorable prognostic factors and to poor clinical outcomes in patients with diffuse large B-cell lymphoma. Hematol Oncol. 2015;33(2):110\u20132. https:\/\/doi.org\/10.1002\/hon.2142.","journal-title":"Hematol Oncol"},{"issue":"11","key":"9537_CR3","doi-asserted-by":"publisher","first-page":"2466","DOI":"10.3109\/10428194.2013.879713","volume":"55","author":"SJ Nam","year":"2014","unstructured":"Nam SJ, et al. An increase of M2 macrophages predicts poor prognosis in patients with diffuse large B-cell lymphoma treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone. Leuk Lymphoma. 2014;55(11):2466\u201376. https:\/\/doi.org\/10.3109\/10428194.2013.879713.","journal-title":"Leuk Lymphoma"},{"issue":"2","key":"9537_CR4","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1111\/j.1365-2559.2011.04096.x","volume":"60","author":"N Wada","year":"2012","unstructured":"Wada N, et al. Tumour-associated macrophages in diffuse large B-cell lymphoma: a study of the Osaka Lymphoma Study Group. Histopathology. 2012;60(2):313\u20139. https:\/\/doi.org\/10.1111\/j.1365-2559.2011.04096.x.","journal-title":"Histopathology"},{"issue":"2","key":"9537_CR5","doi-asserted-by":"publisher","first-page":"238","DOI":"10.3324\/haematol.2014.113472","volume":"100","author":"S Riihijarvi","year":"2015","unstructured":"Riihijarvi S, et al. Prognostic influence of macrophages in patients with diffuse large B-cell lymphoma: a correlative study from a Nordic phase II trial. Haematologica. 2015;100(2):238\u201345. https:\/\/doi.org\/10.3324\/haematol.2014.113472.","journal-title":"Haematologica"},{"issue":"4","key":"9537_CR6","doi-asserted-by":"publisher","first-page":"2317","DOI":"10.1007\/s12032-011-0123-6","volume":"29","author":"QC Cai","year":"2012","unstructured":"Cai QC, et al. High expression of tumor-infiltrating macrophages correlates with poor prognosis in patients with diffuse large B-cell lymphoma. Med Oncol. 2012;29(4):2317\u201322. https:\/\/doi.org\/10.1007\/s12032-011-0123-6.","journal-title":"Med Oncol"},{"key":"9537_CR7","doi-asserted-by":"publisher","first-page":"13","DOI":"10.12703\/P6-13","volume":"6","author":"FO Martinez","year":"2014","unstructured":"Martinez FO, Gordon S. The M1 and M2 paradigm of macrophage activation: time for reassessment. 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Innate immune recognition of cancer. Annu Rev Immunol. 2015;33:445\u201374. https:\/\/doi.org\/10.1146\/annurev-immunol-032414-112043.","journal-title":"Annu Rev Immunol"},{"issue":"1","key":"9537_CR11","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1038\/mt.2011.189","volume":"20","author":"M Fran\u00e7ois","year":"2012","unstructured":"Fran\u00e7ois M, et al. Human MSC suppression correlates with cytokine induction of indoleamine 2,3-dioxygenase and bystander M2 macrophage differentiation. Mol Ther: J Am Soc Gene Ther. 2012;20(1):187\u201395. https:\/\/doi.org\/10.1038\/mt.2011.189.","journal-title":"Mol Ther: J Am Soc Gene Ther"},{"issue":"3","key":"9537_CR12","doi-asserted-by":"publisher","first-page":"424","DOI":"10.1182\/blood-2013-03-488171","volume":"122","author":"K Liapis","year":"2013","unstructured":"Liapis K, et al. 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Derangements of immunological proteins in HIV-associated diffuse large B-cell lymphoma: the frequency and prognostic impact. Front Cell Infect Microbiol. 2024;14:1340096. https:\/\/doi.org\/10.3389\/fcimb.2024.1340096.","journal-title":"Front Cell Infect Microbiol"},{"issue":"614294","key":"9537_CR15","first-page":"2021","volume":"12","author":"A DeRosa","year":"2021","unstructured":"DeRosa A, Leftin A. The iron curtain: macrophages at the interface of systemic and microenvironmental iron metabolism and immune response in cancer. Front Immunol. 2021;12(614294):2021.","journal-title":"Front Immunol"},{"issue":"2","key":"9537_CR16","doi-asserted-by":"publisher","first-page":"426","DOI":"10.1002\/ijc.26397","volume":"131","author":"P Jezequel","year":"2011","unstructured":"Jezequel P, et al. Validation of tumor-associated macrophage ferritin light chain as a prognostic biomarker in node-negative breast cancer tumors: a multicentric 2004 national PHRC study. 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