Fas Ligand on Tumor Cells Mediates Inactivation of Neutrophils

Abstract

The expression of Fas ligand (FasL) on tumor cells (tumor FasL) has been implicated in their evasion of immune surveillance. In this study, we investigated the cellular mechanism for FasL-associated immune escape using melanoma B16F10-derived cells as a model. Transfectants carrying FasL-specific ribozymes expressed low levels of FasL (FasLlow tumor cells) as compared with those carrying enhanced green fluorescent protein-N1 plasmids (FasLhigh tumor cells). When injected s.c. into C57BL/6 mice, FasLlow tumor cells grew more slowly than did FasLhigh melanoma cells. FasLhigh tumor cells showed more intensive neutrophilic infiltration accompanied by multiple necrotizing areas than did FasLlow tumor cells. The average size of FasLlow tumors, but not of FasLhigh tumors, was significantly enhanced in mice depleted of neutrophils. Consistently, a local injection of LPS to recruit/activate neutrophils significantly delayed tumor formation by FasLlow tumor cells, and slightly retarded that of FasLhigh tumor cells in both C57BL/6 and nonobese diabetic/SCID mice. Neutrophils killed FasLlow melanoma cells more effectively than FasLhigh melanoma cells in vitro. The resistance of FasLhigh melanoma cells to being killed by neutrophils was correlated with impaired neutrophil activation, as demonstrated by reductions in gelatinase B secretion, reactive oxygen species production, and the surface expression of CD11b and the transcription of FasL. Local transfer of casein-enriched or PMA-treated neutrophils delayed tumor formation by melanoma cells. Taken together, inactivation of neutrophils by tumor FasL is an important mechanism by which tumor cells escape immune attack.

Depleting Intratumoral CD4+CD25+ Regulatory T Cells via FasL Protein Transfer Enhances the Therapeutic Efficacy of Adoptive T Cell Transfer

“…The antitumor effect of FasL has been shown to be affected by the form (i.e., soluble versus membrane-bound) of FasL expressed on tumors (33). The density of FasL is another contributing factor; tumor cells expressing high levels of FasL have been shown to impair neutrophil activation (34). Under our experimental conditions, FasL-induced neutrophil infiltration has a minimal effect on the antitumor efficacy of adoptive therapy.…”

“…Although it has been shown in certain systems that FasL-mediated neutrophil recruitment can result in antitumor responses (27,30,31), contradicting observations also exist in the literature. The expression of FasL on tumor cells, although capable of inducing intensive neutrophil infiltration of tumor and inflammation, has been shown to fail to cause tumor rejection (33,34). This may be attributed to a few factors.…”

Survival of Virulent Mycobacterium tuberculosis Involves Preventing Apoptosis Induced by Bcl‐2 Upregulation and Release Resulting from Necrosis in J774 Macrophages

“…In recent studies, the expression of FasL in tumor cells was suggested to allow the tumor cells to evade host immune responses by inducing apoptosis in immune cells (4,10). Therefore, it is considered that the upregulation of FasL mRNA in H37Ra-and H37Rv-infected macrophages may be beneficial for M. tuberculosis-infected macrophages to evade killing by immune effector cells.…”

Role of poly(ε-caprolactone) lipid-core nanocapsules on melanoma–neutrophil crosstalk

“…Freshly isolated neutrophils and pretreated tumor cells were cocultured in R10 at 37°C in a humidified CO 2 incubator (5% CO 2 ) for 18 h in 24-well tissue culture plates. To avoid cellto-cell contact, neutrophils were separated from melanoma 32 After 18 h of coculture, neutrophils were removed and melanoma cells were harvested, washed three times, resuspended in PBS and immediately employed in all experiments. Supernatants were also collected and stored at −20°C until the experiments were performed.…”