NK cell activation and tumor infiltration are involved in the antitumor mechanism of Virulizin.
Previous studies have demonstrated antitumor efficacy of Virulizin in several human tumor xenograft models and a critical role for macrophages in the antitumor mechanism of Virulizin. Although there is growing support for an immune stimulatory mechanism of action for Virulizin, the details remain to be elucidated. The aim of this study was to determine whether infiltration of natural killer (NK) cells into xenografted tumors is altered by Virulizin treatment, and whether such alterations contribute to the antitumor activity of Virulizin. Immunohistochemical analysis demonstrated that xenografted tumors from Virulizin-treated mice had an increase in infiltration of F4/80(+) (macrophages) and NK1.1(+) (NK) cells. The increase in NK1.1(+) cell infiltration occurred at an early stage of Virulizin treatment, which correlated with an early sign of apoptosis. In addition, Virulizin resulted in an increase in the number of NK cells in the spleens, and NK cells isolated from the spleen exhibited increased cytotoxicity to tumor cells in vitro. In NK cell-deficient SCID-beige mice, the antitumor activity of Virulizin was compromised, providing additional support to the hypothesis that NK cells are necessary for inhibition of tumor growth by Virulizin. Finally, depletion of macrophages resulted in the loss of Virulizin-induced increase in NK1.1(+) cell infiltration into xenografted tumors, suggesting the involvement of macrophages in NK cell infiltration into tumors. Taken together, these results strongly support a mechanism in which Virulizin stimulates a sustained expansion and infiltration of NK cells and macrophages into tumors with subsequent activation of NK cells that is responsible for the observed antitumor activity.
Cao
Ming Yu
MY
Research and Development Department, Lorus Therapeutics Inc., 2 Meridian Road, Toronto, ON, Canada, M9W 4Z7. mcao@lorusthera.com
Lee
Yoon
Y
Feng
Ningping
N
Li
Hui
H
Du
Caigan
C
Miao
Dengshun
D
Li
Jiarong
J
Lee
Vivian
V
Jin
Hongnan
H
Wang
Ming
M
Gu
Xiaoping
X
Wright
Jim A
JA
Young
Aiping H
AH
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001646:Bile; D045744:Cell Line, Tumor; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology*; D008213:Lymphocyte Activation; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D010455:Peptides / Q000737:chemistry; D013997:Time Factors; D014020:Tissue Extracts
D000276:Adjuvants, Immunologic; D000970:Antineoplastic Agents; D010455:Peptides; D014020:Tissue Extracts; C087098:virulizin