Modulation of TcR/CD3-zeta chain expression by a circulating factor derived from ovarian cancer patients

Abstract

SummaryIn women with ovarian cancer, suppression of components of the immune system may promote tumour development. Previous studies in ovarian cancer have demonstrated that decreased expression and function of the T-cell receptor (TcR)-associated signal transducing zeta-chain correlates with deficient immune responsiveness of T cells. In this study, sera and ascitic fluids obtained from woman with advanced ovarian cancer were found to suppress the expression of TcR-associated zeta chain. This suppression of zeta chain expression was dose-dependent and was not observed with biologic fluids obtained from healthy women.The factor responsible for the loss of zeta chain was purified from ascites and characterized as a protein with an appropriate molecular weight of 14 kD. Suppression of T-cell TcR-zeta was specific, since neither lck nor ZAP-70 expression was affected, while zeta chain was almost completely suppressed. This selective suppression of TcR-zeta expression by the 14 kD ascites-derived factor was shown to operate at the mRNA level. By defining the mechanism through which this protein modulates TcR-zeta chain levels, it might be possible to ultimately prevent the suppressive influences of the tumour microenvironment and restor immune competence in patients with ovarian carcinoma.

Extracellular 2′5′‐oligoadenylate synthetase 2 mediates T‐cell receptor CD3‐ζ chain down‐regulation via caspase‐3 activation in oral cancer

“…26,29,30 The present study reported how extrinsic soluble mediator OAS2 secreted by oral tumour cells modulate CD3-f chain expression in T cells. 38 The 2 0 5 0 -OAS, apart from its antiviral action is involved in other cellular processes such as cell growth and differentiation, gene regulation and apoptosis.…”

Effector CD8+CD45RO−CD27−T cells have signalling defects in patients with squamous cell carcinoma of the head and neck

“…However, in patients with cancer or chronic infections such as leprosy or HIV, z expression may never recover to equal that in normal T cells (Stefanova et al, 1996;Zea et al, 1998), and its absence or partial loss in cancer patients appears to be substantially more common in tumour-infiltrating than in circulating T lymphocytes (Otsuji et al, 1996). Several different mechanisms have been proposed to explain the loss of z expression, including production of reactive oxygen metabolites (ROM) by tumour or tumour-associated monocytes (Kono et al, 1996;Otsuji et al, 1996), or by circulating activated granulocytes (Schmielau and Finn, 2001); apoptosis in the tumour microenvironment (Gastman et al, 1999;Hoffmann et al, 2002;; production and release by the tumour of z inhibitory proteins (Taylor et al, 2001); the availability of L-arginine in the microenvironment (Taheri et al, 2001) or increased degradation of z in chronically activated T cells (Penna et al, 1999). It is interesting to note that the loss of z was observed not only in the CD8 + CD45RA + CD27 À subset of effector cells, but also in other CD8 + T-cell subsets of patients with SCC of the head and neck.…”

Role of prolactin receptor and CD25 in protection of circulating T lymphocytes from apoptosis in patients with breast cancer

“…While the Fas/FasL pathway appears to participate in inducing apoptosis of CD4+ T cells in HIV (Badley et al, 1998) and of CD8+ T cells in cancer (Saito et al, 2000;Dworacki et al, 2001;Hoffmann et al, 2002), it is clearly not the only mechanism responsible for elimination of activated T cells. Among other factors that have been suggested are TNF/TNF-R, TRAIL/TRAIL-R (Srivastava, 2001), tumour-derived soluble factors (Taylor et al, 2001), and reactive oxygen metabolites (Hansson et al, 1999;Schmielau and Finn, 2001). In the case of patients with breast cancer we evaluated, utilisation of sFasL present in the plasma suggests its engagement in Fasmediated apoptosis.…”