Subsets of CD4+ T helper (TH) cells play a major role in maintaining malignant B cells in a dormant state in vivo altering the rate of growth of these cells through the secretion of unique subsets of cytokines. Dormancy is a major feature of clinical cancer and understanding the immunological mechanisms that are responsible for acquisition and maintenance of dormancy in vivo is critically important if long-lasting remission and cure of cancer patients is to be achieved. Knowledge of the immunological mechanisms responsible for maintaining tumor dormancy will be invaluable in the understanding of the events that cause the reactivation of dormant cells in vivo and hence relapse and death from metastatic disease.
The aim of this proposal is to determine the role that CD4+ T helper (TH) cells play in B cell tumor dormancy through the use of cellular immunologic techniques and through the use of several well-characterized models of tumor dormancy in mice. The tumor system chosen is the murine B cell leukemia/lymphoma BCL1 which closely resembles a human prolymphocytic leukemia. It has been established that the BCL1 tumor regresses spontaneously after injection into BALB/c animals that are subsequently immunized with the BCL1 idiotype. 40% of these animals remain disease free for greater than 100 days despite the fact that approximately 2 x 106 dormant BCL1 tumor cells are harbored in their spleens. My working hypothesis is that differences in secretion of particular cytokines by T helper cell clones generated from tumor bearing mice will contribute to tumor growth vs dormancy in the animals. Differences in secreted cytokines may correlate with selective activation/differentiation of a particular TH subset, as has been reported in numerous parasitic diseases and a T cell lymphoma model in mice. In order to test this hypothesis, CD4+ T cell clones will be generated from the spleens of the above-described animals bearing BCL1 tumor, either in an active or a dormant state. The cytokines secreted by these CD4+ TH clones will be analyzed, including IL2, IL3, IL4, IL5, IL10, IFNgamma, tumor necrosis factor and GM-CSF, at both the protein and molecular level. The cytokine secretion patterns of each TH clone will be compared to the patterns seen in non-immunized tumor bearing mice. I would hypothesize that major differences in the levels of IL4, IL5, IL10 and IFNgamma will be observed between the TH clones derived from the animals bearing progressive tumor vs those TH clones derived from animals who are able to maintain the tumor in a dormant state. Based on the results of the TH cloning experiments, immunotherapy aimed at indefinite growth suppression of the tumor, perhaps by affecting the ratio of TH1/TH2 cell in vivo, will be initiated. Plans for immunotherapy include exogenous cytokines, anti-cytokine antibodies and adoptive transfer of """"""""immune"""""""" CD4+ cells.
| Farrar, J D; Street, N E (1995) A synthetic standard DNA construct for use in quantification of murine cytokine mRNA molecules. Mol Immunol 32:991-1000 |
