title: Targeting Macrophages Sensitizes Chronic Lymphocytic Leukemia to Apoptosis and Inhibits Disease Progression.
abstract: The role of monocytes/macrophages in the development and progression of chronic lymphocytic leukemia (CLL) is poorly understood. Transcriptomic analyses show that monocytes/macrophages and leukemic cells cross talk during CLL progression. Macrophage depletion impairs CLL engraftment, drastically reduces leukemic growth, and favorably impacts mouse survival. Targeting of macrophages by either CSF1R signaling blockade or clodrolip-mediated cell killing has marked inhibitory effects on established leukemia also. Macrophage killing induces leukemic cell death mainly via the TNF pathway and reprograms the tumor microenvironment toward an antitumoral phenotype. CSF1R inhibition reduces leukemic cell load, especially in the bone marrow, and increases circulating CD20(+) leukemic cells. Accordingly, co-targeting TAMs and CD20-expressing leukemic cells provides a survival benefit in the mice. These results establish the important role of macrophages in CLL and suggest therapeutic strategies based on interfering with leukemia-macrophage interactions.
authors.affiliation: Unit of Lymphoid Malignancies, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy; Vita-Salute San Raffaele University, 20132 Milan, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Galletti
authors.affiliation: Unit of Lymphoid Malignancies, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy; Vita-Salute San Raffaele University, 20132 Milan, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Scielzo
authors.affiliation: Unit of Lymphoid Malignancies, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Barbaglio
authors.affiliation: Unit of Lymphoid Malignancies, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
authors.forename: Tania Véliz
authors.initials: TV
authors.lastname: Rodriguez
authors.affiliation: Center for Translational Genomics and Bioinformatics, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Riba
authors.affiliation: Center for Translational Genomics and Bioinformatics, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
authors.forename: Dejan
authors.initials: D
authors.lastname: Lazarevic
authors.affiliation: Center for Translational Genomics and Bioinformatics, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Cittaro
authors.affiliation: Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology "L. e A. Seràgnoli," Università di Bologna, 40138 Bologna, Italy.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Simonetti
authors.affiliation: Unit of Lymphoid Malignancies, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
authors.forename: Pamela
authors.initials: P
authors.lastname: Ranghetti
authors.affiliation: Unit of B Cell Neoplasia, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy; Unit of Lymphoid Malignancies, Department of Onco-Hematology, IRCCS San Raffaele Hospital, Milan, Italy.
authors.forename: Lydia
authors.initials: L
authors.lastname: Scarfò
authors.affiliation: Unit of Lymphoid Malignancies, Department of Onco-Hematology, IRCCS San Raffaele Hospital, Milan, Italy; Pathology Unit, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
authors.forename: Maurilio
authors.initials: M
authors.lastname: Ponzoni
authors.affiliation: Unit of Lymphoid Malignancies, Department of Onco-Hematology, IRCCS San Raffaele Hospital, Milan, Italy; Pathology Unit, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
authors.forename: Martina
authors.initials: M
authors.lastname: Rocchi
authors.affiliation: Tumor Biology and Vascular Targeting Unit, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Corti
authors.affiliation: Humanitas Clinical and Research Center, 20089 Rozzano, Milan, Italy.
authors.forename: Achille
authors.initials: A
authors.lastname: Anselmo
authors.affiliation: Department of Molecular Cell Biology, Vrije University Medical Center, 1081 BT Amsterdam, the Netherlands.
authors.forename: Nico
authors.initials: N
authors.lastname: van Rooijen
authors.affiliation: Roche Pharma Research and Early Development, Oncology Discovery, Roche Innovation Center Zurich, 8952 Zurich, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Klein
authors.affiliation: Roche Pharmaceutical Research and Early Development, Roche Innovation Center Penzberg, Oncology Discovery, 82377 Penzberg, Germany.
authors.forename: Carola H
authors.initials: CH
authors.lastname: Ries
authors.affiliation: Vita-Salute San Raffaele University, 20132 Milan, Italy; Unit of B Cell Neoplasia, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy; Unit of Lymphoid Malignancies, Department of Onco-Hematology, IRCCS San Raffaele Hospital, Milan, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Ghia
authors.affiliation: The Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland; Division of Regenerative Medicine, Stem Cells and Gene Therapy, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: De Palma
authors.affiliation: Unit of Lymphoid Malignancies, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy; Vita-Salute San Raffaele University, 20132 Milan, Italy; Unit of Lymphoid Malignancies, Department of Onco-Hematology, IRCCS San Raffaele Hospital, Milan, Italy. Electronic address: federico.caligaris@airc.it.
authors.forename: Federico
authors.initials: F
authors.lastname: Caligaris-Cappio
authors.affiliation: Unit of Lymphoid Malignancies, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy; Vita-Salute San Raffaele University, 20132 Milan, Italy. Electronic address: bertilaccio.sabrina@hsr.it.
authors.forename: Maria Teresa Sabrina
authors.initials: MTS
authors.lastname: Bertilaccio
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology* / Q000473:pathology; D002450:Cell Communication / Q000187:drug effects; D045744:Cell Line, Tumor; D004002:Clodronic Acid / Q000494:pharmacology; D018450:Disease Progression; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000401:mortality; D008081:Liposomes / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D061251:Primary Cell Culture; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D016019:Survival Analysis; D014183:Transplantation, Heterologous; D059016:Tumor Microenvironment / Q000187:drug effects
chemical_list: D000911:Antibodies, Monoclonal; C000604004:Csf1r protein, mouse; D008081:Liposomes; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; D004002:Clodronic Acid