ORIGINAL RESEARCH article

Front. Immunol.

Sec. Cancer Immunity and Immunotherapy

Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1636722

This article is part of the Research TopicNew Avenues for the Development of Advanced Immunotherapies: Capitalizing on Studies of the B and T Cell Receptor RepertoireView all 9 articles

Circulating memory B-cell receptor repertoire identifies novel candidate antibodies against metastatic melanoma in immunotherapy-responsive patients

Provisionally accepted
Fabio NicoliniFabio Nicolini1Anna GaimariAnna Gaimari1,2Lucia MazzottiLucia Mazzotti1,2Anna De LuciaAnna De Lucia1,2Miriana GhirelliMiriana Ghirelli1,2Valentina AncaraniValentina Ancarani1Patricia Borges de SouzaPatricia Borges de Souza1Matteo ZurloMatteo Zurlo1Luca GazzolaLuca Gazzola1,2Chiara MagnoniChiara Magnoni1,2Simona CapobiancoSimona Capobianco1,2Davide AngeliDavide Angeli3Sara BravacciniSara Bravaccini4Claudio CerchioneClaudio Cerchione5Massimo GuidoboniMassimo Guidoboni6Luisa LanfranconeLuisa Lanfrancone7Federica MarocchiFederica Marocchi7Roberta MaltoniRoberta Maltoni8Maria Maddalena TumedeiMaria Maddalena Tumedei2,9Francesco LimarziFrancesco Limarzi10Luigi PasiniLuigi Pasini1*Laura RidolfiLaura Ridolfi1Massimiliano MazzaMassimiliano Mazza1
  • 1Advanced Cellular Therapies and Rare Tumors Unit, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy
  • 2Department of Biomedical and Neuromotor Sciences, Cell Signalling Laboratory, University of Bologna, Bologna, Italy
  • 3Unit of Biostatistics and Clinical Trials, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy
  • 4Department of Medicine and Surgery, "Kore" University of Enna, Enna, Italy
  • 5Hematology Unit, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
  • 6U.O.C. Clinical Oncology, University Hospital of Ferrara, Ferrara, Italy
  • 7Department of Experimental Oncology, European Institute of Oncology IRCCS (IEO), Milan, Italy
  • 8Healthcare Administration, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
  • 9Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
  • 10Pathology Unit, Morgagni-Pierantoni Hospital, AUSL Romagna, Forlì, Italy

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Background By examining the B-cell receptor (BCR) repertoire of metastatic melanoma (MM) patients with favorable treatment outcomes, it is now possible to identify unique patterns of immune responses, with the potential of discovering novel antitumor antibodies. Methods Here, we isolated CD27-positive circulating memory B cells from non responders, partial responders, and complete responders MM patients to first-line therapy with anti-PD-1 immune checkpoint inhibitor (ICI) nivolumab, to perform a BCR repertoire sequencing analysis. We looked for complementarity-determining region 3 (CDR3) sequences that were enriched (de novo formed) following ICI treatment. Fully-human immunoglobulins were then produced in Expi293FF cells using CDR3-sequencing information and tested for specificity and sensitivity on different MM cell lines and patient-derived xenograft cells by flow cytometry and by immunohistochemistry on human tissue microarrays. Results As a result of immunotherapy stimulation in responder patients, we observed that some CDR3 clonotypes have emerged de novo. Among the nine candidate antibodies we assessed, two antibodies exhibited encouraging tumor-targeting properties, although they also showed a degree of cross-reactivity with normal skin and melanocytes. Conclusions Although our study is based on a limited number of individuals, our observations indicate that it may be possible to further investigate the human response to immunotherapy for the identification of rare mature B clonotypes targeting plasma membrane antigens on tumor cells. These preliminary findings could contribute to the future development of fully human-compatible immunotherapies, pending additional validation and in vivo studies.

Keywords: Metastatic Melanoma, Immunotherapy, Responders, B-cell receptor repertoire, patient-derived antibodies, immune checkpoint inhibitors

Received: 28 May 2025; Accepted: 14 Jul 2025.

Copyright: © 2025 Nicolini, Gaimari, Mazzotti, De Lucia, Ghirelli, Ancarani, Borges de Souza, Zurlo, Gazzola, Magnoni, Capobianco, Angeli, Bravaccini, Cerchione, Guidoboni, Lanfrancone, Marocchi, Maltoni, Tumedei, Limarzi, Pasini, Ridolfi and Mazza. This is an open-access article distributed 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) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Luigi Pasini, Advanced Cellular Therapies and Rare Tumors Unit, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, Meldola, Italy

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