F. Pericle et al., IMMUNOCOMPROMISED TUMOR-BEARING MICE SHOW A SELECTIVE LOSS OF STAT5A B EXPRESSION IN T-LYMPHOCYTES AND B-LYMPHOCYTES/, The Journal of immunology, 159(6), 1997, pp. 2580-2585
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.