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

被引：91

作者：

Galletti, Giovanni ^{[1
,2
]}

Scielzo, Cristina ^{[1
,2
]}

Barbaglio, Federica ^{[1
]}

Rodriguez, Tania Veliz ^{[1
]}

Riba, Michela ^{[3
]}

Lazarevic, Dejan ^{[3
]}

Cittaro, Davide ^{[3
]}

Simonetti, Giorgia ^{[4
]}

Ranghetti, Pamela ^{[1
]}

Scarfo, Lydia ^{[5
,6
]}

Ponzoni, Maurilio ^{[6
,7
]}

Rocchi, Martina ^{[6
,7
]}

Corti, Angelo ^{[8
]}

Anselmo, Achille ^{[9
]}

van Rooijen, Nico ^{[10
]}

Klein, Christian ^{[11
]}

Ries, Carola H. ^{[12
]}

Ghia, Paolo ^{[2
,6
]}

De Palma, Michele ^{[13
,14
]}

Caligaris-Cappio, Federico ^{[1
,2
,6
]}

Bertilaccio, Maria Teresa Sabrina ^{[1
,2
]}

机构：

[1] IRCCS San Raffaele Sci Inst, Div Expt Oncol, Unit Lymphoid Malignancies, I-20132 Milan, Italy

[2] Univ Vita Salute San Raffaele, I-20132 Milan, Italy

[3] IRCCS San Raffaele Sci Inst, Ctr Translat Genom & Bioinformat, I-20132 Milan, Italy

[4] Univ Bologna, Inst Hematol L&A Seragnoli, Dept Expt Diagnost & Specialty Med, I-40138 Bologna, Italy

[5] IRCCS San Raffaele Sci Inst, Div Expt Oncol, Unit Cell Neoplasia B, I-20132 Milan, Italy

[6] IRCCS San Raffaele Hosp, Dept Oncohematol, Unit Lymphoid Malignancies, Milan, Italy

[7] IRCCS San Raffaele Sci Inst, Pathol Unit, I-20132 Milan, Italy

[8] IRCCS San Raffaele Sci Inst, Div Expt Oncol, Tumor Biol & Vasc Targeting Unit, I-20132 Milan, Italy

[9] Humanitas Clin & Res Ctr, I-20089 Milan, Italy

[10] Vrije Univ, Med Ctr, Dept Mol Cell Biol, NL-1081 BT Amsterdam, Netherlands

[11] Roche Pharma Res & Early Dev, Oncol Discovery, Roche Innovat Ctr Zurich, CH-8952 Zurich, Switzerland

[12] Roche Pharmaceut Res & Early Dev, Roche Innovat Ctr Penzberg, Oncol Discovery, D-82377 Penzberg, Germany

[13] Ecole Polytech Fed Lausanne, Sch Life Sci, Swiss Inst Expt Canc Res ISREC, CH-1015 Lausanne, Switzerland

[14] IRCCS San Raffaele Sci Inst, Div Regenerat Med Stem Cells & Gene Therapy, I-20132 Milan, Italy

来源：

CELL REPORTS | 2016年 / 14卷 / 07期

关键词：

TUMOR-ASSOCIATED MACROPHAGES; NF-KAPPA-B; CELLS; MICROENVIRONMENT; RECEPTOR; ACTIVATION; ANTIBODY; NOTCH1; MOUSE; CLL;

D O I：

10.1016/j.celrep.2016.01.042

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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 clodrolipmediated 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.

引用

页码：1748 / 1760

页数：13

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