title: Immune tolerance to tumor antigens occurs in a specialized environment of the spleen.
abstract: Peripheral tolerance to tumor antigens (Ags) is a major hurdle for antitumor immunity. Draining lymph nodes are considered the privileged sites for Ag presentation to T cells and for the onset of peripheral tolerance. Here, we show that the spleen is fundamentally important for tumor-induced tolerance. Splenectomy restores lymphocyte function and induces tumor regression when coupled with immunotherapy. Splenic CD11b(+)Gr-1(int)Ly6C(hi) cells, mostly comprising proliferating CCR2(+)-inflammatory monocytes with features of myeloid progenitors, expand in the marginal zone of the spleen. Here, they alter the normal tissue cytoarchitecture and closely associate with memory CD8(+) T cells, cross-presenting tumor Ags and causing their tolerization. Because of its high proliferative potential, this myeloid cell subset is also susceptible to low-dose chemotherapy, which can be exploited as an adjuvant to passive immunotherapy. CCL2 serum levels in cancer patients are directly related to the accumulation of immature myeloid cells and are predictive for overall survival in patients who develop a multipeptide response to cancer vaccines.
authors.affiliation: Department of Surgery, Oncology and Gastroenterology, University of Padua, 35128 Padua, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Ugel
authors.forename: Elisa
authors.initials: E
authors.lastname: Peranzoni
authors.forename: Giacomo
authors.initials: G
authors.lastname: Desantis
authors.forename: Mariacristina
authors.initials: M
authors.lastname: Chioda
authors.forename: Steffen
authors.initials: S
authors.lastname: Walter
authors.forename: Toni
authors.initials: T
authors.lastname: Weinschenk
authors.forename: Jordi C
authors.initials: JC
authors.lastname: Ochando
authors.forename: Anna
authors.initials: A
authors.lastname: Cabrelle
authors.forename: Susanna
authors.initials: S
authors.lastname: Mandruzzato
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Bronte
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D019496:Cancer Vaccines / Q000276:immunology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D006801:Humans; D007108:Immune Tolerance; D007156:Immunologic Memory; D051379:Mice; D009000:Monocytes / Q000276:immunology* / Q000473:pathology; D009369:Neoplasms / Q000276:immunology* / Q000473:pathology; D013154:Spleen / Q000276:immunology* / Q000473:pathology
chemical_list: D000951:Antigens, Neoplasm; D019496:Cancer Vaccines