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Macrophages as effector cells in interleukin 12-induced T cell-dependent tumor rejection.

Abstract
Interleukin (IL)-12 activates a T-cell-dependent antitumor immune response that is able to eradicate established large tumors in a number of immunogenic tumor models. The effector mechanisms in these dramatic antitumor responses have not yet been identified. In this report, we show that the effector mechanism of IL-12-induced rejection of established MCA207 tumors is unique in that it is not dependent on perforin, Fas/Fas ligand, and nitric oxide. Study of cyclophosphamide plus IL-12 (Cy + IL-12)-induced rejection of ascites Sa1 tumor demonstrates that macrophages are the predominant immune cell infiltration in the ascites. These macrophages possess nonspecific tumoricidal activity in vivo as immune distinct MCA207 tumor cells inoculated i.p., but not s.c., in mice bearing regressing Sa1 ascites tumors after Cy + IL-12 therapy are rejected. Furthermore, Cy + IL-12-treated Sa1 ascites cells or macrophages, but not spleen macrophages from the same mouse or inflammatory macrophages induced by thioglycollate, are able to suppress the development of immune-irrelevant s.c. tumors in a Winn assay. These macrophages kill various tumor cells in a contact-dependent manner in vitro, and the cytotoxicity is preserved after fixation with paraformaldehyde. These results demonstrate that activated macrophages function as effector cells in an IL-12-induced, T-cell-dependent eradication of established tumors through a novel contact-dependent, paraformaldehyde fixation-resistant, apoptosis-inducing mechanism.
AuthorsKangla Tsung, James P Dolan, Ying L Tsung, Jeffrey A Norton
JournalCancer research (Cancer Res) Vol. 62 Issue 17 Pg. 5069-75 (Sep 01 2002) ISSN: 0008-5472 [Print] United States
PMID12208763 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S.)
Chemical References
  • Fas Ligand Protein
  • Fasl protein, mouse
  • Membrane Glycoproteins
  • Pore Forming Cytotoxic Proteins
  • Perforin
  • Interleukin-12
  • Cyclophosphamide
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type II
  • Nos2 protein, mouse
Topics
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols (pharmacology)
  • Apoptosis (drug effects, immunology)
  • Cell Communication (immunology)
  • Cyclophosphamide (pharmacology)
  • Cytotoxicity, Immunologic (physiology)
  • Fas Ligand Protein
  • Female
  • Interleukin-12 (immunology, pharmacology)
  • Macrophage Activation (drug effects, immunology)
  • Macrophages (immunology)
  • Membrane Glycoproteins (immunology)
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nitric Oxide Synthase (immunology)
  • Nitric Oxide Synthase Type II
  • Perforin
  • Pore Forming Cytotoxic Proteins
  • Sarcoma, Experimental (drug therapy, immunology)
  • T-Lymphocytes (drug effects, immunology)

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