| Chronic lymphocytic leukemia (CLL) is a B-cell malignancy with a very heterogeneous presentation. Patients with CLL might have either an indolent or aggressive disease course. Although prognostic markers exist to delineate between patients with favorable and unfavorable prognoses, the mechanisms behind progression to aggressive disease remain elusive. The involvement of lymph nodes serves as an unfavorable prognostic marker for CLL; therefore, the differential expression of a set of genes in CLL cells from this site might provide more information as to the biology of CLL cells. The hypothesis of this dissertation was that the upregulation of a tolerogenic signature caused immunosuppression in CLL. The immunosuppression in patients likely presents as an aggressive case of CLL rather than a lackadaisical disease. Gene expression profiles of CLL cells from different sites of the body, including peripheral blood, bone marrow, and lymph node, showed an upregulation of a tolerogenic or immunosuppressive signature in LN-CLL. Of the tolerogenic signature, caveolin-1 (CAV1) was the most highly overexpressed molecule and had previously been reported to contribute to leukemogenesis, but nothing had been reported for CLL. CAV1 knockdown in primary CLL cells impaired CLL cell migration and proliferation. Furthermore, CAV1 knockdown decreased the polymerization of filamentous actin and subsequently immune synapse formation. Lastly, the immunophenotype of Eμ-TCL1 mice was examined during disease progression. In addition to the upregulation of a tolerogenic signature similar to that of CLL patients, Eμ-TCL1 mice had more regulatory T cells compared to controls. These data suggest multiple methods of immunosuppression by CLL cells, including: i.) upregulation of a tolerogenic or immunosuppressive signature, ii.) dysregulation of immune synapse formation, and iii.) increased levels of regulatory or suppressor T cells. In summary, this work describes how CLL cells shape their tumor microenvironment by manipulating both gene expression and the surrounding cells of the immune repertoire to achieve immunosuppression and escape immunosurveillance. |
