Immunocompromised Tumor-Bearing Mice Show a Selective Loss of Stat5a/B Expression in T 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 the advanced stages of tumor growth, loss of immune reactivity has been attributed to the secretion of suppressive cytokines and to tumor-stimulated host immune suppressor T cells or monocytes (3-5). Recently, efforts to explain the decrease in immune responsiveness during tumor growth have focused on molecular defects in T cells isolated from tumor-bearing hosts (6, 7). These studies suggested that the loss of zeta-chain within the TCR-CDS complex contributed to the loss of immune function (6, 7). However, such abnormalities were detectable only at the very end stages of disease and could not account for the immunologic alterations observed during progressive tumor growth (8). Therefore, although a number of mechanisms have been proposed to explain immunosuppression in tumor-bearing hosts, the cause of this phenomenon is still poorly understood. Tumor growth frequently results in the abnormal production of cytokines by the immune system and/or by the tumor itself (9). Cytokines modulate immune cellular responses by transducing biological signals from cell surface receptors to the nucleus through the JAK-STAT signaling pathway (10-12). Ligation of specific cytokine receptors leads to the activation of one or more members of the JAK tyrosine kinase family that constitutively associate with the intracellular domains of the receptor. The activated receptor-kinase complex recruits members of the STAT family of transcription factors to the receptor and phosphorylates them on tyrosine residues. The phosphorylated STAT molecules detach from the receptor, dimerize, translocate into the nucleus, and promote transcriptional activation of cytokine-inducible genes, ultimately controlling cell growth, differentiation, and maintenance of cellular homeostasis. Therefore, STAT proteins are essential components of the cytokine signaling apparatus, contributing to the specificity and diversity of cellular responses to growth factors, peptide hormones, ILs, and cytokines. To date, seven STAT genes (STAT1, 2, 3, 4, 5a, 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 observed 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 tumor-bearing mice were then screened for abnormalities in STAT expression because of their central role in regulating immune function. We present evidence here that STAT5a and STAT5b protein and message are strongly depressed in tumor-bearing mice. In contrast, no changes were observed in the expression of the remaining STATs. [References: 28]

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