Living T9 glioma cells expressing membrane macrophage colony-stimulating factor produce immediate tumor destruction by polymorphonuclear leukocytes and macrophages via a "paraptosis"-induced pathway that promotes systemic immunity against intracranial T9 gliomas.
Cloned T9-C2 glioma cells transfected with membrane macrophage colony-stimulating factor (mM-CSF) never formed subcutaneous tumors when implanted into Fischer rats, whereas control T9 cells did. The T9-C2 cells were completely killed within 1 day through a mechanism that resembled paraptosis. Vacuolization of the T9-C2 cell's mitochondria and endoplasmic reticulum started within 4 hours after implantation. By 24 hours, the dead tumor cells were swollen and terminal deoxynucleotide transferase-mediated dUTP nick-end labeling (TUNEL)-positive. Bcl2-transduced T9-C2 cells failed to form tumors in rats. Both T9 and T9-C2 cells produced cytokine-induced neutrophil chemoattractant that recruited the granulocytes into the tumor injection sites, where they interacted with the tumor cells. Freshly isolated macrophages killed the T9-C2 cells in vitro by a mechanism independent of phagocytosis. Nude athymic rats treated with antiasialo GM1 antibody formed T9-C2 tumors, whereas rats treated with a natural killer cell (NK)-specific antibody failed to form tumors. When treated with antipolymorphonuclear leukocyte (anti-PMN) and antimacrophage antibodies, 80% of nude rats formed tumors, whereas only 40% of the rats developed a tumor when a single antibody was used. This suggests that both PMNs and macrophages are involved in the killing of T9-C2 tumor cells. Immunocompetent rats that rejected the living T9-C2 cells were immune to the intracranial rechallenge with T9 cells. No vaccinating effect occurred if the T9-C2 cells were freeze-thawed, x-irradiated, or treated with mitomycin-C prior to injection. Optimal tumor immunization using mM-CSF-transduced T9 cells requires viable tumor cells. In this study optimal tumor immunization occurred when a strong inflammatory response at the injection of the tumor cells was induced.
Chen
Yijun
Y
Diagnostic and Molecular Health Care Group, Veterans Affairs Medical Center, Long Beach, CA 90822, USA.
Douglass
Thomas
T
Jeffes
Edward W B
EW
Xu
Qingcheng
Q
Williams
Christopher C
CC
Arpajirakul
Neary
N
Delgado
Christina
C
Kleinman
Michael
M
Sanchez
Ramon
R
Dan
Qinghong
Q
Kim
Ronald C
RC
Wepsic
H Terry
HT
Jadus
Martin R
MR
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001932:Brain Neoplasms / Q000276:immunology*; D016923:Cell Death; D019743:Chemokines, CXC; D002630:Chemotactic Factors / Q000502:physiology; D005260:Female; D005615:Freezing; D015870:Gene Expression; D005910:Glioma / Q000276:immunology* / Q000378:metabolism*; D006133:Growth Substances / Q000502:physiology; D006358:Hot Temperature; D007114:Immunization; D020287:In Situ Nick-End Labeling; D036341:Intercellular Signaling Peptides and Proteins; D007694:Killer Cells, Natural / Q000276:immunology; D016173:Macrophage Colony-Stimulating Factor / Q000235:genetics* / Q000502:physiology; D008264:Macrophages / Q000276:immunology*; D008854:Microscopy, Electron; D016685:Mitomycin / Q000494:pharmacology; D009504:Neutrophils / Q000276:immunology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D051381:Rats; D011916:Rats, Inbred F344; D014162:Transfection; D014407:Tumor Cells, Cultured; D014965:X-Rays
D000906:Antibodies; D019743:Chemokines, CXC; D002630:Chemotactic Factors; D006133:Growth Substances; D036341:Intercellular Signaling Peptides and Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016685:Mitomycin; D016173:Macrophage Colony-Stimulating Factor