Characteristics and mechanism of neutrophil-mediated cytostasis induced by tumor necrosis factor

H Shau1

  • 1Division of Surgical Oncology, UCLA Medical Center, Los Angeles, CA 90024.

Insights

Tumor cell growth is suppressed by polymorphonuclear neutrophils (PMN) activated by tumor necrosis factor (TNF). This TNF-induced suppression is mediated by hydrogen peroxide (HP) produced by PMN, not by TNF itself.

Area of Science:

  • Immunology
  • Cell Biology
  • Biochemistry

Background:

  • Tumor necrosis factor (TNF) plays a crucial role in immune responses and inflammation.
  • Polymorphonuclear neutrophils (PMN) are key immune cells involved in host defense.
  • The anti-tumor activity of PMN is an area of active research.

Purpose of the Study:

  • To investigate the mechanism by which TNF-activated PMN suppress tumor cell growth.
  • To determine the role of reactive oxygen species (ROS), specifically hydrogen peroxide (HP), in this suppressive activity.
  • To elucidate the signaling pathway involved in TNF-induced PMN anti-proliferative function.

Main Methods:

  • Treatment of PMN with recombinant TNF (rTNF) and subsequent co-culture with tumor cell lines (Raji, K562, UCLA-SO-M14, U937).
  • Use of neutralizing antibodies against TNF and scavengers for reactive oxygen species (catalase, superoxide dismutase) to assess the role of TNF and HP.
  • Measurement of HP production by PMN and assessment of HP's direct cytostatic effect on tumor cells.

Main Results:

  • TNF-activated PMN exhibited significant suppressive activity against four different tumor cell lines.
  • Neutralization of TNF before PMN activation blocked the anti-proliferative effect.
  • The suppressive activity was dependent on hydrogen peroxide (HP) production by PMN, as indicated by inhibition with catalase.
  • Continuous presence of TNF was not required for the anti-proliferative function after PMN activation.
  • HP alone demonstrated cytostatic effects on Raji cells, but TNF did not enhance Raji cell sensitivity to HP.

Conclusions:

  • TNF-activated PMN induce cytostasis in tumor cells through a mechanism involving hydrogen peroxide (HP).
  • The anti-proliferative effect is mediated by locally high concentrations of HP produced by PMN, rather than by direct action of TNF.
  • These findings highlight a novel mechanism of anti-tumor activity involving PMN and HP, with potential therapeutic implications.

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