Targeting Macrophages Sensitizes Chronic Lymphocytic Leukemia to Apoptosis and Inhibits Disease Progression

Giovanni Galletti; Cristina Scielzo; Federica Barbaglio; Tania Véliz Rodriguez; Michela Riba; Dejan Lazarevic; Davide Cittaro; Giorgia Simonetti; Pamela Ranghetti; Lydia Scarfò; Maurilio Ponzoni; Martina Rocchi; Angelo Corti; Achille Anselmo; Nico van Rooijen; Christian Klein; Carola H. Ries; Paolo Ghia; Michele De Palma; Federico Caligaris-Cappio; Maria Teresa Sabrina Bertilaccio

doi:10.1016/j.celrep.2016.01.042

Targeting Macrophages Sensitizes Chronic Lymphocytic Leukemia to Apoptosis and Inhibits Disease Progression

Giovanni Galletti, Cristina Scielzo, Federica Barbaglio, Tania Véliz Rodriguez, Michela Riba, Dejan Lazarevic, Davide Cittaro, Giorgia Simonetti, Pamela Ranghetti, Lydia Scarfò, Maurilio Ponzoni, Martina Rocchi, Angelo Corti, Achille Anselmo, Nico van Rooijen, Christian Klein, Carola H. Ries, Paolo Ghia, Michele De Palma, Federico Caligaris-CappioMaria Teresa Sabrina Bertilaccio

Research output: Contribution to journal › Article › peer-review

86 Scopus citations

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.

Original language	English (US)
Pages (from-to)	1748-1760
Number of pages	13
Journal	Cell Reports
Volume	14
Issue number	7
DOIs	https://doi.org/10.1016/j.celrep.2016.01.042
State	Published - Feb 23 2016
Externally published	Yes

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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Galletti, G., Scielzo, C., Barbaglio, F., Rodriguez, T. V., Riba, M., Lazarevic, D., Cittaro, D., Simonetti, G., Ranghetti, P., Scarfò, L., Ponzoni, M., Rocchi, M., Corti, A., Anselmo, A., van Rooijen, N., Klein, C., Ries, C. H., Ghia, P., De Palma, M., ... Bertilaccio, M. T. S. (2016). Targeting Macrophages Sensitizes Chronic Lymphocytic Leukemia to Apoptosis and Inhibits Disease Progression. Cell Reports, 14(7), 1748-1760. https://doi.org/10.1016/j.celrep.2016.01.042

Galletti, G, Scielzo, C, Barbaglio, F, Rodriguez, TV, Riba, M, Lazarevic, D, Cittaro, D, Simonetti, G, Ranghetti, P, Scarfò, L, Ponzoni, M, Rocchi, M, Corti, A, Anselmo, A, van Rooijen, N, Klein, C, Ries, CH, Ghia, P, De Palma, M, Caligaris-Cappio, F & Bertilaccio, MTS 2016, 'Targeting Macrophages Sensitizes Chronic Lymphocytic Leukemia to Apoptosis and Inhibits Disease Progression', Cell Reports, vol. 14, no. 7, pp. 1748-1760. https://doi.org/10.1016/j.celrep.2016.01.042

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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.",

author = "Giovanni Galletti and Cristina Scielzo and Federica Barbaglio and Rodriguez, {Tania V{\'e}liz} and Michela Riba and Dejan Lazarevic and Davide Cittaro and Giorgia Simonetti and Pamela Ranghetti and Lydia Scarf{\`o} and Maurilio Ponzoni and Martina Rocchi and Angelo Corti and Achille Anselmo and {van Rooijen}, Nico and Christian Klein and Ries, {Carola H.} and Paolo Ghia and {De Palma}, Michele and Federico Caligaris-Cappio and Bertilaccio, {Maria Teresa Sabrina}",

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doi = "10.1016/j.celrep.2016.01.042",

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T1 - Targeting Macrophages Sensitizes Chronic Lymphocytic Leukemia to Apoptosis and Inhibits Disease Progression

AU - Galletti, Giovanni

AU - Scielzo, Cristina

AU - Barbaglio, Federica

AU - Rodriguez, Tania Véliz

AU - Riba, Michela

AU - Lazarevic, Dejan

AU - Cittaro, Davide

AU - Simonetti, Giorgia

AU - Ranghetti, Pamela

AU - Scarfò, Lydia

AU - Ponzoni, Maurilio

AU - Rocchi, Martina

AU - Corti, Angelo

AU - Anselmo, Achille

AU - van Rooijen, Nico

AU - Klein, Christian

AU - Ries, Carola H.

AU - Ghia, Paolo

AU - De Palma, Michele

AU - Caligaris-Cappio, Federico

AU - Bertilaccio, Maria Teresa Sabrina

PY - 2016/2/23

Y1 - 2016/2/23

N2 - 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.

AB - 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.

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Targeting Macrophages Sensitizes Chronic Lymphocytic Leukemia to Apoptosis and Inhibits Disease Progression

Abstract

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