title: The administration of drugs inhibiting cholesterol/oxysterol synthesis is safe and increases the efficacy of immunotherapeutic regimens in tumor-bearing mice.
abstract: Tumor-derived metabolites dampen tumor-infiltrating immune cells and antitumor immune responses. Among the various metabolites produced by tumors, we recently showed that cholesterol oxidized products, namely oxysterols, favor tumor growth through the inhibition of DC migration toward lymphoid organs and by promoting the recruitment of pro-tumor neutrophils within the tumor microenvironment. Here, we tested different drugs capable of blocking cholesterol/oxysterol formation. In particular, we tested efficacy and safety of different administration schedules, and of immunotherapy-based combination of a class of compounds, namely zaragozic acids, which inhibit cholesterol pathway downstream of mevalonate formation, thus leaving intact the formation of the isoprenoids, which are required for the maturation of proteins involved in the immune cell function. We show that zaragozic acids inhibit the in vivo growth of the RMA lymphoma and the Lewis lung carcinoma (LLC) without inducing side effects. Tumor growth inhibition requires an intact immune system, as immunodeficient tumor-bearing mice do not respond to zaragozic acid treatment. Of note, the effect of zaragozic acids is accompanied by a marked reduction in the LXR target genes Abcg1, Mertk, Scd1 and Srebp-1c in the tumor microenvironment. On the other hand, zoledronate, which blocks also isoprenoid formation, did not control the LLC tumor growth. Finally, we show that zaragozic acids potentiate the antitumor effects of active and adoptive immunotherapy, significantly prolonging the overall survival of tumor-bearing mice treated with the combo zaragozic acids and TAA-loaded DCs. This study identifies zaragozic acids as new antitumor compounds exploitable for the treatment of cancer patients.
authors: Immuno-Biotherapy of Melanoma and Solid Tumors Unit, Division of Experimental Oncology, IRCCS Scientific Institute San Raffaele, Via Olgettina 58, 20132, Milan, Italy.|MolMed S.p.A., Milan, Italy.
authors: Claudia
authors: C
authors: Lanterna
authors: Immuno-Biotherapy of Melanoma and Solid Tumors Unit, Division of Experimental Oncology, IRCCS Scientific Institute San Raffaele, Via Olgettina 58, 20132, Milan, Italy.|Institute for Immunology, Munich, Germany.
authors: Andrea
authors: A
authors: Musumeci
authors: Immuno-Biotherapy of Melanoma and Solid Tumors Unit, Division of Experimental Oncology, IRCCS Scientific Institute San Raffaele, Via Olgettina 58, 20132, Milan, Italy.
authors: Laura
authors: L
authors: Raccosta
authors: Immuno-Biotherapy of Melanoma and Solid Tumors Unit, Division of Experimental Oncology, IRCCS Scientific Institute San Raffaele, Via Olgettina 58, 20132, Milan, Italy.
authors: Gianfranca
authors: G
authors: Corna
authors: Immuno-Biotherapy of Melanoma and Solid Tumors Unit, Division of Experimental Oncology, IRCCS Scientific Institute San Raffaele, Via Olgettina 58, 20132, Milan, Italy.
authors: Marta
authors: M
authors: Moresco
authors: Immuno-Biotherapy of Melanoma and Solid Tumors Unit, Division of Experimental Oncology, IRCCS Scientific Institute San Raffaele, Via Olgettina 58, 20132, Milan, Italy.
authors: Daniela
authors: D
authors: Maggioni
authors: Immuno-Biotherapy of Melanoma and Solid Tumors Unit, Division of Experimental Oncology, IRCCS Scientific Institute San Raffaele, Via Olgettina 58, 20132, Milan, Italy.
authors: Raffaella
authors: R
authors: Fontana
authors: Department of Pathology, IRCCS Scientific Institute San Raffaele, Milan, Italy.|Università Vita-Salute San Raffaele, Milan, Italy.
authors: Claudio
authors: C
authors: Doglioni
authors: Università Vita-Salute San Raffaele, Milan, Italy.|MolMed S.p.A., Milan, Italy.
authors: Claudio
authors: C
authors: Bordignon
authors: MolMed S.p.A., Milan, Italy.
authors: Catia
authors: C
authors: Traversari
authors: Immuno-Biotherapy of Melanoma and Solid Tumors Unit, Division of Experimental Oncology, IRCCS Scientific Institute San Raffaele, Via Olgettina 58, 20132, Milan, Italy. v.russo@hsr.it.
authors: Vincenzo
authors: 0000-0003-1592-5041
authors: V
authors: Russo
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000627:therapeutic use*; D018827:Carcinoma, Lewis Lung / Q000276:immunology / Q000628:therapy*; D002784:Cholesterol / Q000378:metabolism; D003131:Combined Modality Therapy; D003713:Dendritic Cells / Q000276:immunology* / Q000637:transplantation; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D016399:Lymphoma, T-Cell / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D000072376:Oxysterols / Q000378:metabolism; D014233:Tricarboxylic Acids / Q000627:therapeutic use*; D019139:Tumor Escape; D059016:Tumor Microenvironment
chemical_list: D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D000072376:Oxysterols; D014233:Tricarboxylic Acids; C075117:squalestatin 1; D002784:Cholesterol
keywords: Cholesterol; Immune evasion; LXR; Oxysterols; Tumor microenvironment