Cytokine and chemokine expression in tumors of mice receiving systemic therapy with IL-12.
The cellular and molecular mechanisms of IL-12-mediated anti-tumor activity have been examined. BALB/c mice bearing established s.c. RENCA or CT26 tumors that were treated daily with IL-12 showed essentially complete tumor regression while tumors in untreated animals grew progressively. Examination of inflammatory gene expression in tumor tissue from treated vs untreated mice revealed the selective expression of IFN-gamma and the IFN-gamma-inducible CXC chemokine IP-10. Immunohistologic analysis demonstrated that tumors from treated mice were heavily infiltrated with CD8+ T cells and Mac-1+ mononuclear cells. Tumor regression in IL-12-treated mice was associated with expression of the lytic effector molecules perforin and granzyme B. These findings support the hypothesis that the anti-tumor function of IL-12 treatment depends upon the induced expression of IFN-gamma by T cells and/or NK cells, the amplification of the immune response mediated by IFN-gamma-induced expression of chemoattractant cytokines, and the IL-12-dependent potentiation of the cytolytic effector function of recruited CD8+ T cells.
Department of Immunology, Cleveland Clinic Foundation, OH 44195, USA.
C S
CS
Tannenbaum
N
N
Wicker
D
D
Armstrong
R
R
Tubbs
J
J
Finke
R M
RM
Bukowski
T A
TA
Hamilton
D000230:Adenocarcinoma / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D000818:Animals; D002292:Carcinoma, Renal Cell / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D054357:Chemokine CXCL10; D019743:Chemokines, CXC; D002634:Chemotaxis, Leukocyte; D003110:Colonic Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D053804:Granzymes; D007155:Immunologic Factors / Q000627:therapeutic use*; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D018664:Interleukin-12 / Q000627:therapeutic use*; D007680:Kidney Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology* / Q000378:metabolism; D016177:Macrophage-1 Antigen / Q000032:analysis; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D012697:Serine Endopeptidases / Q000096:biosynthesis / Q000235:genetics; D013047:Specific Pathogen-Free Organisms; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism
D054357:Chemokine CXCL10; D019743:Chemokines, CXC; D016207:Cytokines; D007155:Immunologic Factors; D016177:Macrophage-1 Antigen; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D054353:Perforin; D018664:Interleukin-12; D007371:Interferon-gamma; D053804:Granzymes; C509214:Gzmb protein, mouse; D012697:Serine Endopeptidases