title: Low dose gemcitabine-loaded lipid nanocapsules target monocytic myeloid-derived suppressor cells and potentiate cancer immunotherapy.
abstract: Tumor-induced expansion of myeloid-derived suppressor cells (MDSCs) is known to impair the efficacy of cancer immunotherapy. Among pharmacological approaches for MDSC modulation, chemotherapy with selected drugs has a considerable interest due to the possibility of a rapid translation to the clinic. However, such approach is poorly selective and may be associated with dose-dependent toxicities. In the present study, we showed that lipid nanocapsules (LNCs) loaded with a lauroyl-modified form of gemcitabine (GemC12) efficiently target the monocytic (M-) MDSC subset. Subcutaneous administration of GemC12-loaded LNCs reduced the percentage of spleen and tumor-infiltrating M-MDSCs in lymphoma and melanoma-bearing mice, with enhanced efficacy when compared to free gemcitabine. Consistently, fluorochrome-labeled LNCs were preferentially uptaken by monocytic cells rather than by other immune cells, in both tumor-bearing mice and human blood samples from healthy donors and melanoma patients. Very low dose administration of GemC12-loaded LNCs attenuated tumor-associated immunosuppression and increased the efficacy of adoptive T cell therapy. Overall, our results show that GemC12-LNCs have monocyte-targeting properties that can be useful for immunomodulatory purposes, and unveil new possibilities for the exploitation of nanoparticulate drug formulations in cancer immunotherapy.
authors.affiliation: Section of Oncology and Immunology, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy.
authors.forename: Maria Stella
authors.initials: MS
authors.lastname: Sasso
authors.affiliation: LUNAM Université - Micro et Nanomédecines Biomimétiques, F-49933 Angers, France; INSERM U1066, IBS-CHU, 4 Rue Larrey, F-49933 Angers Cedex 9, France.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Lollo
authors.affiliation: LUNAM Université - Micro et Nanomédecines Biomimétiques, F-49933 Angers, France; INSERM U1066, IBS-CHU, 4 Rue Larrey, F-49933 Angers Cedex 9, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Pitorre
authors.affiliation: Section of Oncology and Immunology, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy.
authors.forename: Samantha
authors.initials: S
authors.lastname: Solito
authors.affiliation: Section of Oncology and Immunology, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Pinton
authors.affiliation: Veneto Institute of Oncology IOV-IRCCS, 35128 Padova, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Valpione
authors.affiliation: LUNAM Université - Micro et Nanomédecines Biomimétiques, F-49933 Angers, France; INSERM U1066, IBS-CHU, 4 Rue Larrey, F-49933 Angers Cedex 9, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Bastiat
authors.affiliation: Section of Oncology and Immunology, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35128 Padova, Italy; Veneto Institute of Oncology IOV-IRCCS, 35128 Padova, Italy.
authors.forename: Susanna
authors.initials: S
authors.lastname: Mandruzzato
authors.affiliation: Immunology Section, Department of Medicine, University of Verona, 37135 Verona, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Bronte
authors.affiliation: Veneto Institute of Oncology IOV-IRCCS, 35128 Padova, Italy. Electronic address: ilaria.marigo@ioveneto.it.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Marigo
authors.affiliation: LUNAM Université - Micro et Nanomédecines Biomimétiques, F-49933 Angers, France; INSERM U1066, IBS-CHU, 4 Rue Larrey, F-49933 Angers Cedex 9, France. Electronic address: jean-pierre.benoit@univ-angers.fr.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Benoit
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D006801:Humans; D007165:Immunosuppression Therapy; D007167:Immunotherapy; D016219:Immunotherapy, Adoptive; D008055:Lipids / Q000737:chemistry*; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009000:Monocytes / Q000473:pathology*; D000072737:Myeloid-Derived Suppressor Cells / Q000473:pathology*; D053769:Nanocapsules / Q000737:chemistry*; D009369:Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D010873:Pinocytosis / Q000187:drug effects; D013154:Spleen / Q000473:pathology; D013601:T-Lymphocytes / Q000187:drug effects; D000093542:Gemcitabine
chemical_list: D008055:Lipids; D053769:Nanocapsules; D003841:Deoxycytidine; D000093542:Gemcitabine
keywords: Adoptive T cell therapy; Gemcitabine; Lipid nanocapsules; Myeloid-derived suppressor cells