B cells and macrophages pursue a common path toward the development and progression of chronic lymphocytic leukemia.
The development and progression of chronic B-cell tumors depend on a complex microenvironmental network of cells that include monocyte-derived macrophages. In chronic lymphocytic leukemia (CLL) the survival of malignant cells is supported in vitro by nurse-like cells, which differentiate from CD14+monocytes and have been identified as tumor-associated macrophages (TAMs). The role of the monocyte/macrophage lineage in CLL has been extensively studied in vitro, but only recently has been investigated in in vivo models. We here discuss how the cellular and molecular interactions that physiologically occur between B cells and macrophages can be subverted in chronic B lymphoid malignancies. Clinical approaches for the therapeutic targeting of TAMs are under evaluation. Promising strategies, along with a direct impact on the malignant cells, affect crucial pathways involved in the interaction of leukemic cells with TAMs. As an example, ibrutinib reduces CLL cell chemoattraction by inhibiting macrophage secretion of CXCL13. Lenalidomide and trabectedin prevent TAM recruitment mainly through CCL2 blockade. Most advanced strategies aim at depleting macrophages by targeting the CSF1/CSF1R pathway, which is fundamental for TAM survival. Of note, CSF1 transcripts are significantly more abundant in progressive CLL patients when compared with stable CLL and the frequency of CSF1R+TAMs correlates with poor survival in hematological malignancies. The successful combination of CSF1R inhibition with currently available agents targeting malignant cells might represent the next therapeutic frontier in CLL. Conceivably these approaches may become applicable to numerous chronic B lymphoid malignancies.
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy.|Vita-Salute San Raffaele University, Milan, Italy.
G
G
Galletti
Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy.|Vita-Salute San Raffaele University, Milan, Italy.
F
F
Caligaris-Cappio
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy.|Vita-Salute San Raffaele University, Milan, Italy.
M T S
MT
Bertilaccio
D001402:B-Lymphocytes / Q000473:pathology*; D019070:Cell Lineage; D018450:Disease Progression; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000473:pathology*; D008264:Macrophages / Q000473:pathology*
J Exp Med. 1994 Jun 1;179(6):1895-902
8195715
Blood. 2009 Oct 22;114(17):3625-8
19710503
Leukemia. 2012 Dec;26(12):2538-45
22648449
Biochim Biophys Acta. 2016 Mar;1863(3):401-13
26193078
Curr Opin Immunol. 2006 Feb;18(1):39-48
16337366
Blood. 2009 Nov 12;114(20):4469-76
19755673
Curr Opin Pharmacol. 2015 Aug;23:45-51
26051995
Nat Rev Immunol. 2014 Aug;14 (8):571-8
25033907
Blood. 2005 Sep 15;106(6):2169-74
15933054
Oncogene. 2014 Feb 20;33(8):1006-16
23435417
Cell Death Differ. 2005 Oct;12(10):1319-28
15947793
Cancer Cell. 2015 Apr 13;27(4):462-72
25858805
Blood. 2010 Nov 11;116(19):3955-63
20682855
Nature. 2007 Nov 1;450(7166):110-4
17934446
Blood. 2013 Dec 5;122(24):3960-3
24100449
Proc Natl Acad Sci U S A. 2009 Apr 14;106(15):6250-5
19332800
Leuk Res. 2009 Oct;33(10):1319-27
19395025
Nat Rev Immunol. 2009 Jan;9(1):15-27
19079135
Leuk Lymphoma. 2014 Nov;55(11):2466-76
24397616
Immunity. 2007 Jul;27(1):160-71
17658276
Nature. 1995 Sep 7;377(6544):68-71
7659164
Nat Med. 2015 Oct;21(10):1209-15
26322579
Histopathology. 2012 Jan;60(2):313-9
22211289
Blood. 2012 Aug 16;120(7):1412-21
22547582
Science. 2000 May 26;288(5470):1439-41
10827957
Blood. 2014 Mar 13;123(11):1709-19
24464016
J Clin Invest. 2008 Jul;118(7):2427-37
18551193
Eur J Immunol. 2010 Aug;40(8):2296-307
20468007
Semin Cancer Biol. 2014 Feb;24:71-81
24018164
Cancer Res. 2010 Jul 15;70(14):5728-39
20570887
Semin Cancer Biol. 2014 Feb;24:23-32
23978491
J Immunol. 2009 Feb 15;182(4):2113-23
19201864
Immunity. 2014 Jul 17;41(1):49-61
25035953
Blood. 2015 Jan 1;125(1):111-23
25368373
Proc Natl Acad Sci U S A. 2002 May 14;99(10 ):6955-60
12011454
Cell. 2009 Jul 23;138(2):286-99
19632179
Blood. 2009 Oct 15;114(16):3367-75
19636060
J Immunol. 1983 Oct;131(4):1714-27
6619542
Br J Haematol. 2012 Aug;158(3):336-46
22583117
Blood. 2000 Oct 15;96(8):2655-63
11023495
J Exp Med. 1996 Nov 1;184(5):1927-37
8920880
J Biol Chem. 2016 Jul 1;291(27):14356-62
27226587
Clin Cancer Res. 2016 Jan 1;22(1):86-95
26283682
Hematology Am Soc Hematol Educ Program. 2011;2011:96-103
22160019
Cell. 2010 Sep 3;142(5):699-713
20813259
Trends Immunol. 2002 Nov;23(11):549-55
12401408
Nat Rev Immunol. 2012 Mar 22;12(4):253-68
22437938
PLoS One. 2015 Jun 12;10(6):e0125203
26066800
Blood. 2010 Nov 18;116(20):4223-30
20660791
Blood. 2013 Jan 31;121(5):812-21
23118218
Cancer Cell. 2005 Sep;8(3):211-26
16169466
J Immunol. 1995 Apr 15;154(8):3863-70
7706726
Int Immunol. 2001 Sep;13(9):1193-201
11526100
Blood. 2012 Feb 23;119(8):1810-20
22186992
Cancer Cell. 2014 Jun 16;25(6):846-59
24898549
Leukemia. 2013 Mar;27(3):702-10
22996336
Eur J Immunol. 1992 Mar;22(3):711-7
1547817
Blood. 2005 Apr 15;105(8):3042-50
15613544
Br J Haematol. 2009 Nov;147(4):471-83
19751240
Blood. 2002 Feb 1;99(3):1030-7
11807009
J Leukoc Biol. 2009 Nov;86(5):1065-73
19741157
Haematologica. 2011 Mar;96(3):408-16
21134984
PLoS One. 2010 Dec 30;5(12):e15992
21209908
Nature. 1992 Apr 16;356(6370):612-5
1348572
Immunology. 1986 Jun;58(2):285-90
3519443
Cell. 2007 Nov 16;131(4):641-3
18022354
Clin Cancer Res. 2016 Apr 1;22(7):1572-82
26660519
Leuk Lymphoma. 2013 Oct;54(10):2112-21
23432691
Immunity. 2014 Jul 17;41(1):14-20
25035950
EMBO Rep. 2012 Sep;13(9):798-810
22868664
Science. 1999 Jul 9;285(5425):260-3
10398604
PLoS One. 2013;8(3):e60370
23555960
Eur J Immunol. 2015 Mar;45(3):747-57
25487358
Blood. 2008 May 15;111(10):5173-81
18326821
Int Rev Immunol. 2001 Feb;20(1):137-55
11342302
PLoS One. 2013 May 08;8(5):e62805
23667522
Science. 2015 Feb 6;347(6222):667-72
25657250
J Immunol. 2001 Nov 1;167(9):5052-60
11673514
Nat Immunol. 2009 Jul;10(7):786-93
19503106
Blood. 2005 Aug 1;106(3):1012-20
15860672
J Innate Immun. 2012;4(5-6):424-36
22488251
J Immunol. 2011 Feb 15;186(4):2172-81
21257969
Blood. 2011 May 19;117(20):5403-12
21444914
Cancer Cell. 2013 Mar 18;23(3):277-86
23518347
Immunity. 2007 Jun;26(6):703-14
17582343
Haematologica. 2011 Feb;96(2):269-76
21071500
Cancer Cell. 2013 Feb 11;23 (2):249-62
23410977
Blood. 2002 Sep 1;100(5):1795-801
12176902
Nat Rev Cancer. 2004 Jan;4(1):71-8
14708027
Blood. 2008 Aug 1;112(3):840-3
18519815
Science. 2001 Sep 14;293(5537):2111-4
11509691
Leuk Lymphoma. 2012 Mar;53(3):417-23
21879809
J Immunol. 2013 May 15;190(10):4923-7
23567932
Cell Rep. 2016 Feb 23;14 (7):1748-60
26876171
MAbs. 2015;7(2):303-10
25667985
Blood. 2003 Jun 1;101(11):4464-71
12531790
Oncoimmunology. 2014 Dec 13;3(9):e955356
25941615
J Exp Med. 2006 Mar 20;203(3):583-97
16492803
Cancer Cell. 2014 Jun 16;25(6):809-21
24909985
Nat Immunol. 2007 Sep;8(9):992-1000
17660822
Blood. 2009 Mar 26;113(13):3050-8
19074730
Trends Immunol. 2010 Jun;31(6):212-9
20452821
Blood Cells Mol Dis. 2013 Apr;50(4):263-70
23313631
Trends Immunol. 2015 Apr;36(4):229-39
25770924
N Engl J Med. 2010 Mar 11;362(10):875-85
20220182
Immunology. 2004 Nov;113(3):348-54
15500621
Nat Rev Immunol. 2008 Dec;8(12):958-69
19029990
J Immunol. 2004 Apr 15;172(8):4717-23
15067047
Immunity. 2012 Mar 23;36(3):415-26
22386268
Leukemia. 2012 Jan;26(1):139-48
21788945
Immunol Cell Biol. 2009 Jan;87(1):30-8
19048016
Science. 2013 Aug 9;341(6146):670-3
23868921
Lancet Oncol. 2015 Aug;16(8):949-56
26179200
Blood. 2007 Nov 1;110(9):3316-25
17652619
Annu Rev Immunol. 2015;33:643-75
25861979
Blood. 2013 Mar 28;121(13):2503-11
23349394
Leukemia. 2016 Mar;30(3):570-9
26522085
Semin Immunol. 2002 Dec;14(6):371-6
12457609
Crit Rev Oncol Hematol. 2008 Apr;66(1):1-9
17913510
Clin Cancer Res. 2016 Dec 15;22(24):6118-6128
27334834
J Clin Oncol. 2008 Mar 20;26(9):1544-52
18285605
Nat Rev Mol Cell Biol. 2011 Feb;12(2):79-89
21252997
Leuk Lymphoma. 2013 Aug;54(8):1826-30
23848063
Cancer Discov. 2014 Dec;4(12 ):1448-65
25252690