Human B Cells Mediate Innate Anti-Cancer Cytotoxicity Through Concurrent Engagement of Multiple TNF Superfamily Ligands

• Published in: Frontiers in immunology Vol. 13; p. 837842
• Main Authors: Janjic, Bratislav M, Kulkarni, Aditi, Ferris, Robert L, Vujanovic, Lazar, Vujanovic, Nikola L
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 22-03-2022
• Subjects: Apoptosis Regulatory Proteins; B cells; B-Lymphocytes; cancer; cytotoxic; head and neck squamous cell carcinoma; Humans; Immunology; innate immunity; Ligands; Neoplasms; TNF superfamily ligands; TNF-Related Apoptosis-Inducing Ligand; Tumor Necrosis Factor-alpha - metabolism; TNF superfamily ligands; innate immunity; cancer; B cells; single-cell RNA sequencing (scRNAseq); cytotoxic; head and neck squamous cell carcinoma
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2022.837842

The essential innate immunity effector cells, natural killer and dendritic cells, express multiple plasma membrane-associated tumor necrosis factor (TNF) superfamily (TNFSF) ligands that, through simultaneous and synergistic engagement, mediate anti-cancer cytotoxicity. Here, we report that circulating B cells, mediators of adaptive humoral immunity, also mediate this innate anti-cancer immune mechanism. We show that resting human B cells isolated from peripheral blood induce apoptosis of, and efficiently kill a large variety of leukemia and solid tumor cell types. Single-cell RNA sequencing analyses indicate, and flow cytometry data confirm that B cells from circulation express transmembrane TNF, Fas ligand (FasL), lymphotoxin (LT) α1β2 and TNF-related apoptosis-inducing ligand (TRAIL). The cytotoxic activity can be inhibited by individual and, especially, combined blockade of the four transmembrane TNFSF ligands. B cells from tumor-bearing head and neck squamous cell carcinoma patients express lower levels of TNFSF ligands and are less cytotoxic than those isolated from healthy individuals. In conclusion, we demonstrate that B cells have the innate capacity to mediate anti-cancer cytotoxicity through concurrent activity of multiple plasma membrane-associated TNFSF ligands, that this mechanism is deficient in cancer patients and that it may be part of a general cancer immunosurveillance mechanism.