Abstract
T cells from cancer patients are often functionally impaired, which imposes a barrier to effective immunotherapy. Most pronounced are the alterations characterizing tumor-infiltrating T cells, which in renal cell carcinomas includes defective NF-kappaB activation and a heightened sensitivity to apoptosis. Coculture experiments revealed that renal tumor cell lines induced a time-dependent decrease in RelA(p65) and p50 protein levels within both Jurkat T cells and peripheral blood T lymphocytes that coincided with the onset of apoptosis. The degradation of RelA/p50 is critical for SK-RC-45-induced apoptosis because overexpression of RelA in Jurkat cells protects against cell death. The loss of RelA/p50 coincided with a decrease in expression of the NF-kappaB regulated antiapoptotic protein Bcl-xL at both the protein and mRNA level. The disappearance of RelA/p50 protein was mediated by a caspase-dependent pathway because pretreatment of T lymphocytes with a pan caspase inhibitor before coculture with SK-RC-45 blocked RelA and p50 degradation. SK-RC-45 gangliosides appear to mediate this degradative pathway, as blocking ganglioside synthesis in SK-RC-45 cells with the glucosylceramide synthase inhibitor, PPPP, protected T cells from tumor cell-induced RelA degradation and apoptosis. The ability of the Bcl-2 transgene to protect Jurkat cells from RelA degradation, caspase activation, and apoptosis implicates the mitochondria in these SK-RC-45 ganglioside-mediated effects.
Highlights
Both tumor-infiltrating lymphocytes (TIL) and peripheral blood T cells isolated from renal cell carcinoma (RCC) patients exhibit impaired NF-B activation and increased sensitivity to apoptosis [16, 19]
The inhibitory effect of tumor cells on Jurkat cell NF-B activation was paralleled by tumor-induced apoptosis of the lymphocytes (38%) as compared with smooth muscle cell (SMC), which did not mediate Jurkat cell apoptosis above the 5% background levels (Fig. 1B)
Our study illustrates a potential mechanism by which renal cell carcinoma lines induce apoptosis in T cells
Summary
TIL, tumor-infiltrating lymphocyte; RCC, renal cell carcinoma; HA, hemagglutinin; SMC, smooth muscle cell; -Gus, -glucuronidase; PPPP, 1-phenyl-2-hexadecanoylamino-3-pyrrolidino-1-propanol. RelA expression is a critical event in tumor-induced apoptosis of T cells as demonstrated by the ability of RelA overexpression to protect Jurkat cells from decreased expression of Bcl-xL and apoptosis mediated by coculture with SK-RC-45. The mechanism of tumor-induced degradation of RelA/p50 involves a caspase-dependent pathway because inhibitors of caspase activity prevented disappearance of Rel proteins and abrogated T cell killing. Our studies support the notion that tumor-derived gangliosides are important mediators of NF-B inhibition and induction of apoptosis, because blocking ganglioside expression in RCC by pretreatment with the glucosylceramide synthase inhibitor, 1-phenyl-2hexadecanoylamino-3-pyrrolidino-1-propanol (PPPP), prevented both NF-B inactivation and initiation of apoptosis by tumor
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