Collapse of the CD27+ B-cell compartment associated with systemic plasmacytosis in patients with advanced melanoma and other cancers.
OBJECTIVE
Disturbed peripheral blood B-cell homeostasis complicates certain infections and autoimmune diseases, such as HIV and systemic lupus erythematosus, but has not been reported in cancer. This study aimed to investigate whether B-cell physiology was altered in the presence of melanoma and other cancers.


METHODS
Flow cytometry was used to identify phenotypic differences in B cells from patients with melanoma and normal donors. In vitro stimulated B cells were assessed for responsiveness and also used as stimulators of allogeneic T cells in mixed lymphocyte reactions.


RESULTS
We show B-cell dysregulation in patients with advanced melanoma (n = 26) and other solid tumors (n = 13), marked by a relative and absolute loss of CD27+ (memory) B cells and associated with an aberrant systemic plasmacytosis. Functionally, B cells from patients with melanoma inefficiently up-regulated immunoregulatory molecules and weakly secreted cytokines in response to CD40 and toll-like receptor 9 agonists. Stimulated B cells from patients induced proliferation of alloreactive CD4+ T cells, but these T cells poorly secreted IFNgamma and interleukin-2. These effects were recapitulated by using purified normal donor CD27(neg) B cells in these same assays, linking the predominance of CD27(neg) B cells in patients with the observed functional hyporesponsiveness. Indeed, B-cell dysfunction in patients strongly correlated with the extent of loss of CD27+ B cells in peripheral blood.


CONCLUSIONS
Disturbed B-cell homeostasis is a previously unrecognized feature of patients with advanced melanoma and other cancers and may represent an unanticipated mechanism of immune incompetence in cancer.
Carpenter
Erica L
EL
Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Mick
Rosemarie
R
Rech
Andrew J
AJ
Beatty
Gregory L
GL
Colligon
Theresa A
TA
Rosenfeld
Myrna R
MR
Kaplan
David E
DE
Chang
Kyong-Mi
KM
Domchek
Susan M
SM
Kanetsky
Peter A
PA
Fecher
Leslie A
LA
Flaherty
Keith T
KT
Schuchter
Lynn M
LM
Vonderheide
Robert H
RH
D000328:Adult; D017209:Apoptosis / Q000276:immunology; D001402:B-Lymphocytes / Q000378:metabolism* / Q000473:pathology* / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000637:transplantation; D018450:Disease Progression; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D018655:Lymphocyte Count; D008545:Melanoma / Q000150:complications / Q000276:immunology* / Q000473:pathology; D009369:Neoplasms / Q000150:complications / Q000276:immunology*; D010950:Plasma Cells / Q000378:metabolism / Q000473:pathology*; D014184:Transplantation, Homologous; D019139:Tumor Escape / Q000276:immunology; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000378:metabolism*
C508594:IL2 protein, human; D007376:Interleukin-2; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D007371:Interferon-gamma