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Prepublished online as a Blood First Edition Paper on July 5, 2002; DOI 10.1182/blood-2002-01-0174.
Submitted January 24, 2002
Accepted April 4, 2002
Living T9 Glioma Cells Expressing Membrane Macrophage Colony Stimulating Factor (mM-CSF) Produce Immediate Tumor Destruction by Polymorphonuclear Leukocytes and Macrophages via a Paraptosis-Induced Pathway that Promotes Systemic Immunity Against Intracranial T9 Gliomas
Yijun Chen, Thomas Douglass, Edward W Jeffes, Qingcheng Xu, Christopher C Williams, Neary Arpajirakul, Christina Delgado, Michael Kleinman, Ramon Sanchez, Qinghong Dan, Ronald C Kim, Terry Wepsic, and Martin R Jadus*
Diagnostic and Molecular Health Care Group, VA Medical Center, Long Beach, CA, USA; Pathology Department, University of California, Irvine, Irvine, CA, USA
Biological Sciences Department, California State University Long Beach, Long Beach, CA, USA
Dermatology Service, VA Medical Center, Long Beach, CA, USA; Deparment of Dermatology, University of California Irvine, Irvine, CA, USA
Department of Community and Environmental Medicine, University of California, Irvine, Irvine, CA, USA
* Corresponding author; email: martin.jadus{at}med.va.gov.
Cloned membrane macrophage colony stimulating factor (mM-CSF) transfected T9-C2 glioma cells never formed subcutaneous tumors when implanted into Fischer rats, while control T9 cells did. The T9-C2 cells were completely killed within one 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 TUNEL positive. Bcl-2-transduced T9-C2 cells failed to form tumors in rats. Both T9 and T9-C2 cells produced cytokine-induced neutrophil chemoattractant (CINC), which 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 cell contact-dependent mechanism, independent of phagocytosis. Nude athymic rats treated with anti-asialo GM1 antibody formed T9-C2 tumors; whereas, rats treated with an NK-specific antibody failed to form tumors. Anti-polymorphonuclear leukocytes (PMNs) and anti-macrophage antibody treated nude rats formed tumors in 80% of the animals, 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 against the intracranial rechallenge with T9 cells. No vaccinating effect occurred if the T9-C2 cells were freeze-thawed, x-irradiated or mitomycin-C treated prior to injection. Optimal tumor immunization using mM-CSF transduced T9 cells requires viable tumor cells and occurred when a strong inflammatory response at the injection of the tumor cells was induced.
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