title: Differently immunogenic cancers in mice induce immature myeloid cells that suppress CTL in vitro but not in vivo following transfer.
abstract: Tumors frequently induce immature myeloid cells (iMC), which suppress specific and unrelated cytotoxic T lymphocyte (CTL) responses and are termed myeloid-derived suppressor cells (MDSC). Mainly analyzed by in vitro assays in tumor transplantation models, little is known about their function in autochthonous tumor models in vivo. We analyzed iMC in 3 SV40 large T (Tag)-driven conditional autochthonous cancer models with different immune status: (1) Early Tag-specific CTL competence and rare stochastic Tag activation leading to sporadic cancer, which induces an aberrant immune response and CTL tolerance; (2) Cre/LoxP recombinase-mediated hepatocellular carcinoma (HCC) development in neonatal Tag-tolerant mice; and (3) Tag-activation through Cre recombinase-encoding viruses in the liver and HCC development with systemic anti-Tag CTL immunity. In the first but not two latter models, tumors induced CTL hyporesponsiveness to tumor-unrelated antigens. Regardless of the model, tumors produced interleukin-6 and vascular endothelial growth factor but not granulocyte macrophage–colony-stimulating factor (GM-CSF) and induced iMC (CD11b(+)Gr-1(int)) that suppressed CTL responses in vitro. None of the iMC from the different tumor models suppressed CTL responses in adoptive cell transfer experiments unless GM-CSF was provided in vivo. Together, iMC expand independent of the type of antitumor response and are not immunosuppressive in a cell-autonomous fashion.
authors.affiliation: Institute of Immunology, Charité Campus Buch, Berlin, Germany.
authors.forename: Karin
authors.initials: K
authors.lastname: Schmidt
authors.forename: Serena
authors.initials: S
authors.lastname: Zilio
authors.forename: Jan C
authors.initials: JC
authors.lastname: Schmollinger
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Bronte
authors.forename: Thomas
authors.initials: T
authors.lastname: Blankenstein
authors.forename: Gerald
authors.initials: G
authors.lastname: Willimsky
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D017951:Antigen Presentation; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D006528:Carcinoma, Hepatocellular / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000097:blood; D005434:Flow Cytometry; D006801:Humans; D007108:Immune Tolerance; D007114:Immunization; D066298:In Vitro Techniques; D019426:Integrases / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism / Q000473:pathology
chemical_list: D000952:Antigens, Polyomavirus Transforming; D016207:Cytokines; C045073:Cre recombinase; D019426:Integrases