B cell profiles, antibody repertoire and reactivity reveal dysregulated responses with autoimmune features in melanoma

Silvia Crescioli, Isabel Correa, Joseph Ng, Zena N Willsmore, Roman Laddach, Alicia Chenoweth, Jitesh Chauhan, Ashley Di Meo, Alexander Stewart, Eleni Kalliolia, Elena Alberts, Rebecca Adams, Robert J Harris, Silvia Mele, Giulia Pellizzari, Anna B M Black, Heather J Bax, Anthony Cheung, Mano Nakamura, Ricarda M HoffmannManuela Terranova-Barberio, Niwa Ali, Ihor Batruch, Antoninus Soosaipillai, Ioannis Prassas, Antigona Ulndreaj, Miyo K Chatanaka, Rosamund Nuamah, Shichina Kannambath, Pawan Dhami, Jenny L C Geh, Alastair D MacKenzie Ross, Ciaran Healy, Anita Grigoriadis, David Kipling, Panagiotis Karagiannis, Deborah K Dunn-Walters, Eleftherios P Diamandis, Sophia Tsoka, James Spicer, Katie E Lacy, Franca Fraternali, Sophia N Karagiannis

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

Abstract

B cells are known to contribute to the anti-tumor immune response, especially in immunogenic tumors such as melanoma, yet humoral immunity has not been characterized in these cancers to detail. Here we show comprehensive phenotyping in samples of circulating and tumor-resident B cells as well as serum antibodies in melanoma patients. Memory B cells are enriched in tumors compared to blood in paired samples and feature distinct antibody repertoires, linked to specific isotypes. Tumor-associated B cells undergo clonal expansion, class switch recombination, somatic hypermutation and receptor revision. Compared with blood, tumor-associated B cells produce antibodies with proportionally higher levels of unproductive sequences and distinct complementarity determining region 3 properties. The observed features are signs of affinity maturation and polyreactivity and suggest an active and aberrant autoimmune-like reaction in the tumor microenvironment. Consistent with this, tumor-derived antibodies are polyreactive and characterized by autoantigen recognition. Serum antibodies show reactivity to antigens attributed to autoimmune diseases and cancer, and their levels are higher in patients with active disease compared to post-resection state. Our findings thus reveal B cell lineage dysregulation with distinct antibody repertoire and specificity, alongside clonally-expanded tumor-infiltrating B cells with autoimmune-like features, shaping the humoral immune response in melanoma.

Original languageEnglish
Article number3378
JournalNature Communications
Volume14
Issue number1
DOIs
Publication statusPublished - 8 Jun 2023

Keywords

  • Humans
  • B-Lymphocytes
  • Melanoma/genetics
  • Antibodies
  • Immunity, Humoral
  • Autoantigens/genetics
  • Tumor Microenvironment

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