title: Successful colon cancer eradication after chemoimmunotherapy is associated with profound phenotypic change of intratumoral myeloid cells.
abstract: IL-12 is a potent immunostimulatory cytokine, but its impact as an antitumor drug in clinical practice is limited. Upsurge of regulatory T cells (Treg) in the tumor milieu has been proposed to limit the efficacy of the treatment. In this paper, two drugs (cyclophosphamide [CPA] and anti-CD25 mAb) widely used to eliminate Treg were used in an attempt to enhance the antitumor effect of IL-12 gene therapy. Both anti-CD25 and CPA combined with IL-12 were able to deplete intratumoral Treg and myeloid-derived suppressor cells (MDSC), but only IL-12 plus CPA achieved significant antitumor activity in mice with large established s.c. colon carcinoma. This therapeutic effect was associated with the emergence of a heterogeneous population of myeloid cells within the tumor, termed inflammatory myeloid cells (IMC), composed of Ly6C(high)Ly6G(low) inflammatory monocytes and Ly6G(high)Ly6C(+) neutrophils. IMC showed a distinctive pattern of cytokine/chemokine production, and in contrast to MDSC, they did not induce conversion of naive CD4(+) T cells into Treg. The appearance of IMC coincided with intense tumor infiltration by effector T cells, which was abrogated by elimination of IMC by anti-Gr1 mAb, a maneuver that abolished the antitumor effect of the therapy. Therefore, the combination of IL-12 and CPA eliminates intratumoral Treg and MDSC, while it induces the appearance of IMC within the tumor microenvironment. The latter effect is essential to facilitate effector T cell infiltration and subsequent tumor elimination.
authors.affiliation: Division of Hepatology and Gene Therapy, Center for Applied Medical Research, University of Navarra, Pamplona, 31008 Navarra, Spain.
authors.forename: José
authors.initials: J
authors.lastname: Medina-Echeverz
authors.forename: Jessica
authors.initials: J
authors.lastname: Fioravanti
authors.forename: Maider
authors.initials: M
authors.lastname: Zabala
authors.forename: Nuria
authors.initials: N
authors.lastname: Ardaiz
authors.forename: Jesús
authors.initials: J
authors.lastname: Prieto
authors.forename: Pedro
authors.initials: P
authors.lastname: Berraondo
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000627:therapeutic use; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000008:administration & dosage; D005260:Female; D015316:Genetic Therapy / Q000379:methods; D016130:Immunophenotyping; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D018664:Interleukin-12 / Q000008:administration & dosage / Q000235:genetics / Q000627:therapeutic use; D053645:Interleukin-2 Receptor alpha Subunit / Q000037:antagonists & inhibitors / Q000276:immunology; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000276:immunology / Q000473:pathology; D022423:Myeloid Cells / Q000187:drug effects / Q000276:immunology* / Q000473:pathology*; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D009504:Neutrophils / Q000276:immunology / Q000473:pathology; D013154:Spleen / Q000276:immunology / Q000473:pathology
chemical_list: D000911:Antibodies, Monoclonal; D053645:Interleukin-2 Receptor alpha Subunit; D018664:Interleukin-12; D003520:Cyclophosphamide