Using a murine mammary tumor syngeneic to BALB/c mice (D1-DMBA-3) we have previously documented profound changes in the immune system correlating with increasing tumor burden. Some of the phenotypic and functional alterations are due to, at least in part, to the production of immunomodulatory cytokines by the tumor. We have shown that GM-CSF is constitutively produced by the D1-DMBA-3 tumor and that it promotes the appearance and/or expansion of a population of aberrant macrophages capable of downregulating the immune responses of tumor bearing mice. The proposed studies will analyze whether animals implanted with preneoplastic lesions from which the D1-DMBA-3 tumor was derived, also display altered parameters of immunity. Likewise, the immune responses of these mice after progression of the preneoplastic lesions to established neoplasia will be studied. These phenotypic and functional characterizations will be performed not only using cells of the peripheral organs but also with tumor-infiltrating lymphoreticular cells. The production of cytokines, such as GM-CSF, by the preneoplastic lesions or mammary tumors developed from then in BALB/c mice, will be assessed. Likewise, the causes for the loss of tumoricidal potential of peritoneal exudate macrophages from tumor bearing mice will be studied. The mechanisms of downregulation of GM-CSF- induced macrophages present in mammary tumors (and in preneoplastic lesions if they occur) will be explored. Although GM-CSF is used to replenish depleted bone marrow cells after chemotherapy and radiation, the long term consequences of such treatment are unknown. Therefore, the elucidation of the role of this molecule in the immune system of mice bearing preneoplastic or tumor tissues will lead to a rational approach to the administration of this factor to cancer patients. furthermore, these studies will provide new insight into the modulatory effects of the immune responses in the progression from preneoplasia to fully developed neoplasms.
