Journal
CLINICAL CANCER RESEARCH
Volume 15, Issue 13, Pages 4277-4287Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-09-0537
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Funding
- NIH [CA093372, CA09140, CA16520, AI47519, RR017625]
- Breast Cancer Research Foundation
- VA Career Development Award
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Purpose: 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. Experimental Design: Flow cytometry was used to identify phenotypic differences in B cells from patients with melanoma and normal donors. In vitro stimulated 8 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 IFN gamma 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.
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