IMMUNOCOMPROMISED TUMOR-BEARING MICE SHOW A SELECTIVE LOSS OF STAT5A B EXPRESSION IN T-LYMPHOCYTES AND B-LYMPHOCYTES/

Progression of tumor growth in experimental animals and in patients is frequently associated with a decline in immune function (1, 2). In th e advanced stages of tumor growth, loss of immune reactivity has been attributed to the secretion of suppressive cytokines and to tumor-stim ulated host immune suppressor T cells or monocytes (3-5). Recently, ef forts to explain the decrease in immune responsiveness during tumor gr owth have focused on molecular defects in T cells isolated from tumor- bearing hosts (6, 7). These studies suggested that the loss of zeta-ch ain within the TCR-CDS complex contributed to the loss of immune funct ion (6, 7). However, such abnormalities were detectable only at the ve ry end stages of disease and could not account for the immunologic alt erations observed during progressive tumor growth (8). Therefore, alth ough a number of mechanisms have been proposed to explain immunosuppre ssion in tumor-bearing hosts, the cause of this phenomenon is still po orly understood. Tumor growth frequently results in the abnormal produ ction of cytokines by the immune system and/or by the tumor itself (9) . Cytokines modulate immune cellular responses by transducing biologic al signals from cell surface receptors to the nucleus through the JAK- STAT signaling pathway (10-12). Ligation of specific cytokine receptor s leads to the activation of one or more members of the JAK tyrosine k inase family that constitutively associate with the intracellular doma ins of the receptor. The activated receptor-kinase complex recruits me mbers of the STAT family of transcription factors to the receptor and phosphorylates them on tyrosine residues. The phosphorylated STAT mole cules detach from the receptor, dimerize, translocate into the nucleus , and promote transcriptional activation of cytokine-inducible genes, ultimately controlling cell growth, differentiation, and maintenance o f cellular homeostasis. Therefore, STAT proteins are essential compone nts of the cytokine signaling apparatus, contributing to the specifici ty and diversity of cellular responses to growth factors, peptide horm ones, ILs, and cytokines. To date, seven STAT genes (STAT1, 2, 3, 4, 5 a, 5b, and 6) have been identified (10-12). STAT5a and STAT5b are two closely related genes that presumably arose by gene duplication (13). The purpose of the current report was to investigate molecular changes in lymphoid cells that could explain the loss of immune functions obs erved in tumor-bearing mice. In this study, we first showed that mice bearing a syngeneic mammary adenocarcinoma (TS/A) displayed loss of Ag -specific T cell responsiveness and Ab production. Lymphocytes from tu mor-bearing mice were then screened for abnormalities in STAT expressi on because of their central role in regulating immune function. We pre sent evidence here that STAT5a and STAT5b protein and message are stro ngly depressed in tumor-bearing mice. In contrast, no changes were obs erved in the expression of the remaining STATs.