[en] The immune tumor microenvironment is a dynamic ecosystem where B cells play critical roles in modulating immune checkpoint blockade (ICB) therapy responses. While traditionally seen as passive players in tumor immunity, recent evidence suggests that B cells actively influence antitumor responses. This study examines the role of B cells and their extracellular vesicles (EVs) in melanoma responses to ICB. Retrospective meta-analyses reveal increased B cell enrichment in ICB responders' pretreatment. Functional assays show that B cell depletion impairs T cell-mediated tumor cytotoxicity. EVs from melanoma tumors were analyzed, identifying miR-99a-5p in CD19+ EVs as up-regulated in responders. Silencing miR-99a-5p in B cells reduces T cell antitumor activity, suggesting its role in immune modulation. Mechanistically, miR-99a-5p promotes B cell maturation via class-switch recombination. These findings underscore B cells' impact on melanoma immunotherapy, offering insights into novel therapeutic strategies targeting B cell-related pathways.
Al Hrout, Ala'a ; Institute of Experimental Immunology, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland
Balayev, Agshin; Institute of Experimental Immunology, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland
Cervantes-Gracia, Karla; Institute of Experimental Immunology, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland
Gkelis, Konstantinos; Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH Zurich), 8093 Zurich, Switzerland
Benke, Stephan ; Flow Cytometry Facility, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland
Matínez Gómez, Julia M ; Department of Dermatology, University Hospital Zurich, University of Zurich, 8091 Zurich, Switzerland
Silina, Karina ; Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH Zurich), 8093 Zurich, Switzerland
Levesque, Mitchell P ; Department of Dermatology, University Hospital Zurich, University of Zurich, 8091 Zurich, Switzerland
CHAHWAN, Richard ; University of Luxembourg ; Institute of Experimental Immunology, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland ; EVIIVE AG, 8057 Zurich, Switzerland
External co-authors :
yes
Language :
English
Title :
B cell extracellular vesicles influence melanoma response to immune checkpoint therapy.
Publication date :
10 October 2025
Journal title :
Science Advances
eISSN :
2375-2548
Publisher :
American Association for the Advancement of Science, United States
R.C. has been supported by grants from SNF (310030_212553, 320030E_215576, CRSK-3_ 190550, IZSEZ0_204655, and IZSEZ0_218166), Novartis Foundation (22B140), Vontobel Stiftung (41309), UZH-STWF (F-41309\u2013 01-01), and UZH-URPP (Translational Cancer Research). K.S. has been supported by Prima grant (PR00P3_201656). Funding for open access charge: SNSF-C hronoshubAcknowledgments: We thank all members of the melanoma biobank at USZ for help and feedback; UZH flow cytometry facility for continuous support; J. Riemann and UZH microscopy facility for teM analysis; and c. M\u00FCnz, i. Arnold, and O. chijoke for critical reading of the manuscript. Funding: R.c. has been supported by grants from SnF (310030_212553, 320030e_215576, cRSK-3_190550, iZSeZ0_204655, and iZSeZ0_218166), novartis Foundation (22B140), vontobel Stiftung (41309), UZH-StWF (F-41309\u201301-01), and UZH-URPP (translational cancer Research). K.S. has been supported by Prima grant (PR00P3_201656). Funding for open access charge: SnSF-chronoshub. Authors contributions: conceptualization: A.A., R.c., and M.P.l. Methodology: A.A., K.S. K.G., R.c., M.P.l., and A.B. Software: A.B. validation: A.A., K.c.-G., R.c., M.P.l., and A.B. Formal analysis: A.A., K.S., S.B., R.c., and A.B. investigation: A.A., K.G., R.c., and A.B. Resources: K.S., J.M.M.G., R.c., M.P.l., and A.B. data curation: A.A., K.S., J.M.M.G., R.c., and A.B. Writing\u2014original draft: A.A. Writing\u2014review and editing: A.A., K.S., J.M.M.G., R.c., M.P.l., and A.B. visualization: A.A. and R.c. Supervision: A.A., K.S., R.c., and M.P.l. Project administration: A.A., K.S., R.c., and M.P.l. Funding acquisition: K.S., R.c., and M.P.l. Competing interests: K.S. is a paid consultant at Memo therapeutics AG, Switzerland. R.c. is cofounder of eviive AG, Switzerland. All other authors declare that they have no competing interests. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials and deposited in GeO (GSe274664).
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