Abstract
The pathogenic impact of tumor-infiltrating B cells is unresolved at present, however, some studies suggest that they may have immune regulatory potential. Here, we report that the microenvironment of various solid tumors includes B cells that express granzyme B (GrB, GZMB), where these B cells can be found adjacent to interleukin (IL)-21-secreting regulatory T cells (Treg) that contribute to immune tolerance of tumor antigens. Because Tregs and plasmacytoid dendritic cells are known to modulate T-effector cells by a GrB-dependent mechanism, we hypothesized that a similar process may operate to modulate regulatory B cells (Breg). IL-21 induced outgrowth of B cells expressing high levels of GrB, which thereby limited T-cell proliferation by a GrB-dependent degradation of the T-cell receptor ζ-chain. Mechanistic investigations into how IL-21 induced GrB expression in B cells to confer Breg function revealed a CD19(+)CD38(+)CD1d(+)IgM(+)CD147(+) expression signature, along with expression of additional key regulatory molecules including IL-10, CD25, and indoleamine-2,3-dioxygenase. Notably, induction of GrB by IL-21 integrated signals mediated by surface immunoglobulin M (B-cell receptor) and Toll-like receptors, each of which were enhanced with expression of the B-cell marker CD5. Our findings show for the first time that IL-21 induces GrB(+) human Bregs. They also establish the existence of human B cells with a regulatory phenotype in solid tumor infiltrates, where they may contribute to the suppression of antitumor immune responses. Together, these findings may stimulate novel diagnostic and cell therapeutic approaches to better manage human cancer as well as autoimmune and graft-versus-host pathologies.
Highlights
It is widely recognized that certain B-cell subpopulations exhibit potent regulatory properties and are involved in immune pathologies including autoimmune and malignantAuthors' Affiliations: Institutes of 1Transfusion Medicine, 2Pharmacology of Natural Products and Clinical Pharmacology, and 3Pathology; Departments of 4Gynecology and Obstetrics and 5Pediatrics, Ulm University; 6Institute for Clinical Transfusion Medicine and Immunogenetics, Red Cross Blood Service Baden-Wu€rttemberg–Hessen, Ulm; Institutes of 7Applied Physics and 8Toxicology and Genetics, 9Center for Functional Nanostructures, Karlsruhe Institute of Technology (KIT), Karlsruhe, Germany; and 10Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, AustraliaNote: Supplementary data for this article are available at Cancer Research Online.K
We show that IL-21 induces a regulatory phenotype in human B cells with expression of immunoregulatory molecules including granzyme B (GrB), IL-10, indoleamine-2,3-dioxygenase (IDO), and CD25
IL-21 rapidly induced expression and secretion of enzymatically active GrB in a number of B cells, an effect strongly enhanced by simultaneous B-cell receptor (BCR) stimulation (Fig. 1A and B and Supplementary Fig. S1)
Summary
It is widely recognized that certain B-cell subpopulations exhibit potent regulatory properties and are involved in immune pathologies including autoimmune and malignant. Authors' Affiliations: Institutes of 1Transfusion Medicine, 2Pharmacology of Natural Products and Clinical Pharmacology, and 3Pathology; Departments of 4Gynecology and Obstetrics and 5Pediatrics, Ulm University; 6Institute for Clinical Transfusion Medicine and Immunogenetics, Red Cross Blood Service Baden-Wu€rttemberg–Hessen, Ulm; Institutes of 7Applied Physics and 8Toxicology and Genetics, 9Center for Functional Nanostructures, Karlsruhe Institute of Technology (KIT), Karlsruhe, Germany; and 10Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Australia. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). This work is part of the scientific and doctoral theses of S.
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