Lymphocyte response and dysregulation in human cancer
Abstract
Although it is now widely accepted that tumors exert influence on and are influenced by the immune system, the functional inter-relationship between cancer and specific immune system subsets is less well understood, especially in human cancer patients. To evaluate this, a comprehensive panel of immunoassays was used to phenotypically and functionally analyze peripheral blood B and CD8+ T cells in 46 patients with various types of solid tumors. I first explored the hypothesis that CD8+ T cells mediate effective immunosurveillance of tumors in paraneoplastic cerebellar degeneration (PCD), a disease in which a T cell-mediated immune response is thought to occur to cdr-2, an antigen co-expressed by tumor and Purkinje neurons. In contrast to a prevailing notion in the field, my assessment of the prevalence and function of tumor antigen-specific CD8+ T cells in 7 PCD patients revealed no evidence for a role of cdr2-specific CD8+ T cells, despite detection of PCD-associated B cell activation. Next, I studied the peripheral blood of 39 patients with melanoma and other advanced solid tumors to explore the hypothesis that the presence of cancer has an immunosubversive effect on circulating B cells. Although the role of B cells has been clearly demonstrated in many paraneoplastic diseases such as PCD, the broader impact of cancer on B cells is not well studied. My assays revealed significantly lower numbers of CD27+ memory B cells as well as systemic plasmacytosis, providing evidence of previously unrecognized dysregulation of B cell pathophysiology in cancer. Melanoma patient B cells were also hyporesponsive to activation via CD40 and TLR9. CD40/TLR9-stimulated patient B cells induced alloreactive CD4+ T cell proliferation comparable to that induced by normal donor B cells but patient B cell-induced CD4+ T cell IFN-γ and IL-2 secretion was significantly lower. Altered B cell function in patients worsened with the presence of active disease and strongly correlated with diminished CD27+ B cells. lsolated CD27neg B cells from normal donors largely recapitulated these deficits. In summary, these results suggest that dysfunctional B cells may represent an unanticipated tumor-dependent mechanism of immune incompetence.
Subject Area
Immunology
Recommended Citation
Erica L Carpenter,
"Lymphocyte response and dysregulation in human cancer"
(January 1, 2009).
Dissertations available from ProQuest.
Paper AAI3363263.
http://repository.upenn.edu/dissertations/AAI3363263
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