title: Increased numbers of monocyte-derived dendritic cells during successful tumor immunotherapy with immune-activating agents.
abstract: Local treatment with selected TLR ligands or bacteria such as bacillus Calmette-Guérin increases antitumor immune responses and delays tumor growth. It is thought that these treatments may act by activating tumor-associated dendritic cells (DCs), thereby supporting the induction of antitumor immune responses. However, common parameters of successful immune activation have not been identified. We used mouse models to compare treatments with different immune-activating agents for the ability to delay tumor growth, improve priming of tumor-specific T cells, and induce early cytokine production and DC activation. Treatment with polyinosinic-polycytidylic acid or a combination of monosodium urate crystals and Mycobacterium smegmatis was effective at delaying the growth of s.c. B16 melanomas, orthotopic 4T1 mammary carcinomas, and reducing 4T1 lung metastases. In contrast, LPS, monosodium urate crystals, or M. smegmatis alone had no activity. Effective treatments required both NK1.1(+) and CD8(+) cells, and resulted in increased T cell priming and the infiltration of NK cells and CD8(+) T cells in tumors. Unexpectedly, both effective and ineffective treatments increased DC numbers and the expression of costimulatory molecules in the tumor-draining lymph node. However, only effective treatments induced the rapid appearance of a population of monocyte-derived DCs in the draining lymph node, early release of IL-12p70 and IFN-γ, and low IL-10 in the serum. These results suggest that the activation of existing DC subsets is not sufficient for the induction of antitumor immune responses, whereas early induction of Th1 cytokines and monocyte-derived DCs are features of successful activation of antitumor immunity.
authors.affiliation: Malaghan Institute of Medical Research, Wellington 6242, New Zealand.
authors.forename: Sabine
authors.initials: S
authors.lastname: Kuhn
authors.forename: Evelyn J
authors.initials: EJ
authors.lastname: Hyde
authors.forename: Jianping
authors.initials: J
authors.lastname: Yang
authors.forename: Fenella J
authors.initials: FJ
authors.lastname: Rich
authors.forename: Jacquie L
authors.initials: JL
authors.lastname: Harper
authors.forename: Joanna R
authors.initials: JR
authors.lastname: Kirman
authors.forename: Franca
authors.initials: F
authors.lastname: Ronchese
mesh_terms: D056704:Adaptive Immunity; D000276:Adjuvants, Immunologic / Q000627:therapeutic use*; D000818:Animals; D001691:Biological Therapy; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002277:Carcinoma / Q000276:immunology / Q000556:secondary / Q000628:therapy*; D002452:Cell Count; D002454:Cell Differentiation / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D003713:Dendritic Cells / Q000276:immunology*; D004926:Escherichia coli / Q000276:immunology; D005260:Female; D007167:Immunotherapy; D016219:Immunotherapy, Adoptive; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000097:blood; D018664:Interleukin-12 / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology*; D008175:Lung Neoplasms / Q000517:prevention & control / Q000556:secondary; D008198:Lymph Nodes / Q000473:pathology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D008546:Melanoma, Experimental / Q000276:immunology / Q000556:secondary / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009000:Monocytes / Q000187:drug effects / Q000276:immunology*; D020102:Mycobacterium smegmatis / Q000276:immunology*; D010047:Ovalbumin / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology; D011070:Poly I-C / Q000494:pharmacology* / Q000627:therapeutic use; D011828:Radiation Chimera; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000637:transplantation; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D014527:Uric Acid / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000276:Adjuvants, Immunologic; D016207:Cytokines; C556062:IL10 protein, mouse; C110366:OVA-8; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; D016753:Interleukin-10; D018664:Interleukin-12; D014527:Uric Acid; D007371:Interferon-gamma; D010047:Ovalbumin; D011070:Poly I-C