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

Abstract

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.

Human papillomavirus infection can alter the level of tumour stemness and T cell infiltration in patients with head and neck squamous cell carcinoma

“…The scRNA-seq data of patients with HNSCC were obtained from the GEO database (GSE164690) ( 8 ). The data were integrated using the SCTransform method of R software Seurat package and analysed using mutual principal component analysis (PCA).…”

Targets of tumor microenvironment for potential drug development

“…Janjic and colleagues demonstrated that the resting human B lymphocytes derived from peripheral blood can induce efficient killing of leukemia and solid tumor cells. 61 B cells from the circulation expressed transmembrane tumor necrosis factor (TNF) superfamily (TNFSF) ligand, including TNF, Fas ligand, lymphotoxin (LT) α1β2, and TNF-related apoptosis-inducing ligand (TRAIL). Evidence showed that B cells from patients with head and neck squamous cell carcinoma (HNSCC) expressed decreased levels of TNFSF ligands and exhibited reduced cytotoxicity compared to those from healthy individuals.…”

“…Evidence showed that B cells from patients with head and neck squamous cell carcinoma (HNSCC) expressed decreased levels of TNFSF ligands and exhibited reduced cytotoxicity compared to those from healthy individuals. 61 Recent studies have demonstrated B cell maturation antigen (BCMA), also known as tumor necrosis factor receptor superfamily member 17 (TNFRSF17) and CD269, was preferentially expressed in mature B cells, and its overexpression and activation were related to multiple myeloma (MM) development. The conversion of membrane-bound BCMA to soluble BCMA (sBCMA) through the action of γ-secretase was noteworthy, especially since higher serum levels of sBCMA have been observed in MM patients, where it correlates with poorer prognosis.…”

“…B cells are multifunctional components of the immune system, with capabilities extending to antibody secretion, antigen presentation, cytokine production, and the establishment of immunological memory. Janjic and colleagues demonstrated that the resting human B lymphocytes derived from peripheral blood can induce efficient killing of leukemia and solid tumor cells 61 . B cells from the circulation expressed transmembrane tumor necrosis factor (TNF) superfamily (TNFSF) ligand, including TNF, Fas ligand, lymphotoxin (LT) α1β2, and TNF‐related apoptosis‐inducing ligand (TRAIL).…”

Antibody Diversity in Cancer: Translational Implications and Beyond

“…This secretion, in turn, could contribute to Th1/Th2 polarization of T cells or boost the responses of T cells [ 37 ]. Furthermore, the possible defensive effect of B cells in cancer is shown by CpG-activated B cells that utilize TNF-related apoptosis inducing ligand (TRAIL/Apo-2L)-dependent mechanisms to attack tumor cells [ 38 , 39 ]. The existence of this function of mediating anti-cancer cytotoxicity is further strengthened by the induction of an increase in granzyme B levels in B-chronic lymphocytic leukemia cells when treated with IL-21 and CpG oligodeoxynucleotide [ 39 , 40 ].…”