Immunohistological analysis of immune cell infiltration of a human colon tumor xenograft after treatment with Stealth liposome-encapsulated tumor necrosis factor-alpha and radiation.
The toxicity associated with tumor necrosis factor-alpha (TNF-alpha) has limited its usefulness as an anticancer agent. However, encapsulation of TNF-alpha in Stealth (SL) liposomes can minimize risk for toxicity and thus increase its potential as an adjuvant treatment. Our recent studies have shown that SL-TNF-alpha plus radiation is more effective at inhibiting LS174T colon tumor growth than either radiation alone or free TNF-alpha plus radiation. This increase in efficacy was coincident with a modulation of immune parameters in blood and spleen. The aim of this study was to determine if infiltration of natural killer (NK) cells, macrophages, and neutrophils into LS174T tumors was altered by SL-TNF-alpha treatment and whether any observed changes could potentially contribute to the enhanced antitumor efficacy seen with SL-TNF-alpha plus radiation treatment. Sections of excised tumors were examined histologically and quantitative analysis was performed using laser scanning cytometry. The data showed that the group receiving multiple treatments with SL-TNF-alpha plus radiation had the smallest tumors, but yet the level of necrosis was similar to that found in groups with much larger tumors. Furthermore, the necrotic areas in the SL-TNF-alpha plus radiation group had signs of recent and/or continuing cell death and the highest levels of NK cell and macrophage infiltrates. In time course experiments, a single injection of SL-TNF-alpha (but not free TNF-alpha) induced fluctuations in leukocyte infiltration into tumors that correlated inversely with our previous findings in blood and spleen. Overall, the data indicate that the mechanisms underlying the increased efficacy of SL-TNF-alpha compared to free TNF-alpha include a rapid and relatively sustained recruitment of NK cells, macrophages, and neutrophils.
Kim
Dong W
DW
Department of Radiation Medicine, Radiobiology Program, Chan Shun Pavilion, Loma Linda University and Medical Center, Loma Linda, CA 92354, USA. dkim03m2@som.llu.edu
Andres
Melba L
ML
Miller
Glen M
GM
Cao
Jeffrey D
JD
Green
Lora M
LM
Seynhaeve
Ann L B
AL
Ten Hagen
Timo L M
TL
Gridley
Daila S
DS
D000818:Animals; D003110:Colonic Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D003131:Combined Modality Therapy; D006801:Humans; D007150:Immunohistochemistry; D007694:Killer Cells, Natural / Q000502:physiology; D008081:Liposomes; D008264:Macrophages / Q000502:physiology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009504:Neutrophils / Q000502:physiology; D014183:Transplantation, Heterologous; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage*
D008081:Liposomes; D014409:Tumor Necrosis Factor-alpha