17
Onco
l
Vol 7
l
Nr 3
l
2013
Omzetting van MO-MDSC's naar TAM's
MO-MDSC's uit de milt kunnen in vitro sterk immuunsuppres-
sieve en M2-georiënteerde macrofagen vormen (37). Daaren-
boven kunnen MO-MDSC's, die aanwezig zijn in de tumor, zich
differentiëren tot macrofagen bij blootstelling aan hypoxie (20).
Voorts kunnen TDSF's, zoals heat shock protein 27 (HSP27), bij
monocyten (en waarschijnlijk ook bij MO-MDSC), de differenti-
atie opwekken naar macrofagen, die zeer angiogeen zijn en een
immuunsuppressief fenotype bevatten (38). MO-MDSC's kun-
nen echter ook differentiëren in macrofagen met antitumuraal
fenotype (39), wat de veelzijdigheid van deze cellen benadrukt.
Omzetting van TADC's naar TAM's
DC-precursoren en monocyten infiltreren tumoren en kunnen
vervolgens verder differentiëren naar verschillende immunogene
DC-substes. In de tumormicro-omgeving kunnen echter verschil-
lende mechanismen deze differentiatie verhinderen. Zo werd on-
der meer aangetoond dat tumorgeassocieerde cytkonines, zoals
IL-10, de differentiatie van monocyten in DC's kunnen verhinderen
en ze eerder laten differentiëren naar macrofagen (40).
Net zoals macrofagen, kunnen DC's ook voorkomen in verschil-
lende functionele toestanden die samen met de tumor evolueren.
Zo werd in een carcinoommodel bij muizen aangetoond dat DC's
zeer immunogeen zijn tijdens de vroege fasen van tumorvorming,
terwijl deze cellen in latere stadia evolueren naar een immuunsup-
pressief fenotype (MHC II
laag
CD40
laag
PDL1
hoog
) (41).
Globaal genomen tonen deze data aan dat de micro-omgeving
van de tumor de differentiatie van myeloïde (voorloper)cellen
naar macrofagen sterk promoot. Dit kan een verklaring zijn
voor waarom TAM's de voornaamste tumorgeassocieerde my-
eloïde celpopulatie is. Tevens bevestigt dit ook het belang van
TAM's in tumorprogressie.
Conclusie
Tumoren zijn complexe en dynamische structuren die
geïnfiltreerd worden door verscheidene immuuncellen, waarbij
myeloïde cellen vaak overheersen. Deze tumorgeassocieerde
myeloïde cellen spelen door hun immuunsuppressieve en
angiogene capaciteiten een belangrijke rol bij tumorprogressie
en metastase. Hoopgevend is echter dat deze capaciteiten
opgewekt worden door gemeenschappelijke mechanismen,
signalisatiewegen en factoren. Hierdoor vormen deze myeloïde
cellen de basis van nieuwe therapeutische interventies die als
doel hebben hun tumorbevorderend fenotype te moduleren.
Verder onderzoek naar de plasticiteit van deze cellen is
echter nodig om een beter inzicht te krijgen over hun
activerings-toestanden, differentiatiemogelijkheden en inter-
cellulaire omzettingen.
Referenties
1.
Swartz MA, Iida N, Roberts EW, et al. Tumor microenvironment complexity: emerging roles in
cancer therapy. Cancer Res 2012;72(10):2473-80.
2.
Mantovani A, Sica A. Macrophages, innate immunity and cancer: balance, tolerance and diversity.
Curr Opin Immunol 2010;22(2):231-7.
3.
Peinado H, Lavotshkin S, Lyden D. The secreted factors responsible for pre-metastatic niche
formation: old sayings and new thoughts. Semin Cancer Biol 2011;21(2):139-46.
4.
Motz GT, Coukos G. The parallel lives of angiogenesis and immunosuppression: cancer and
other tales. Nat Rev Immunol 2011;11(10):702-11.
5.
Laoui D, Van Overmeire E, Movahedi K, et al. Mononuclear phagocyte heterogeneity in cancer:
different subsets and activation states reaching out at the tumor site. Immunobiology
2011;216(11):1192-202.
6.
Sica A, Bronte V. Altered macrophage differentiation and immune dysfunction in tumor deve-
lopment. J Clin Invest 2007;117(5):1155-66.
7.
Kurahara H, Shinchi H, Mataki Y, et al. Significance of M2-polarized tumor-associated macro-
phage in pancreatic cancer. J Surg Res 2011;167(2):e211-9.
8.
Movahedi K, Laoui D, Gysemans C, et al. Different tumor microenvironments contain function-
ally distinct subsets of macrophages derived from Ly6C(high) monocytes. Cancer Res
2010;70(14):5728-39.
9.
Coffelt SB, Tal AO, Scholz A, et al. Angiopoietin-2 regulates gene expression in TIE2-expressing
monocytes and augments their inherent proangiogenic functions. Cancer Res
2010;70(13):5270-80.
10. Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune
system. Nat Rev Immunol 2009;9(3):162-74.
11. Filipazzi P, Huber V, Rivoltini L. Phenotype, function and clinical implications of myeloid-derived
suppressor cells in cancer patients. Cancer Immunol Immunother 2012;61(2):255-63.
12. Movahedi K, Guilliams M, Van den Bossche J, et al. Identification of discrete tumor-induced
myeloid-derived suppressor cell subpopulations with distinct T cell-suppressive activity. Blood
2008;111(8):4233-44.
13. Guilliams M, Henri S, Tamoutounour S, et al. From skin dendritic cells to a simplified classifica-
tion of human and mouse dendritic cell subsets. Eur J Immunol 2010;40(8):2089-94.
14. Joffre O, Nolte MA, Spörri R, Reis e Sousa C. Inflammatory signals in dendritic cell activation
and the induction of adaptive immunity. Immunol Rev 2009;227(1):234-47.
15. Gregory AD, Houghton AM. Tumor-associated neutrophils: new targets for cancer therapy.
Cancer Res 2011;71(7):2411-6.
16. Fridlender ZG, Sun J, Kim S, et al. Polarization of tumor-associated neutrophil phenotype by
TGF-beta: `N1' versus `N2' TAN. Cancer Cell 2009;16(3):183-94.
17. Wenger RH. Cellular adaptation to hypoxia: O2-sensing protein hydroxylases, hypoxia-induci-
ble transcription factors, and O2-regulated gene expression. FASEB J 2002;16(10):1151-62.
18. Du R, Lu KV, Petritsch C, et al. HIF1alpha induces the recruitment of bone marrow-derived
vascular modulatory cells to regulate tumor angiogenesis and invasion. Cancer Cell
2008;13(3):206-20.
19. Fang H-Y, Hughes R, Murdoch C, et al. Hypoxia-inducible factors 1 and 2 are important
transcriptional effectors in primary macrophages experiencing hypoxia. Blood
2009;114(4):844-59.
20. Corzo CA, Condamine T, Lu L, et al. HIF-1 regulates function and differentiation of myeloid-
derived suppressor cells in the tumor microenvironment. J Exp Med 2010;207(11):2439-53.
21. Zhang K, Shen X, Wu J, et al. Endoplasmic reticulum stress activates cleavage of CREBH to
induce a systemic inflammatory response. Cell 2006;124(3):587-99.
22. Mahadevan NR, Zanetti M. Tumor stress inside out: Cell-extrinsic effects of the unfolded
protein response in tumor cells modulate the immunological landscape of the tumor microen-
vironment. J Immunol 2011;187(9):4403-9.
23. Xiang X, Poliakov A, Liu C, et al. Induction of myeloid-derived suppressor cells by tumor
exosomes. Int J Cancer 2009;124(11):2621-33.
24. Chalmin F, Ladoire S, Mignot G, et al. Membrane-associated Hsp72 from tumor-derived exoso-
mes mediates STAT3-dependent immunosuppressive function of mouse and human myeloid-
derived suppressor cells. J Clin Invest 2010;120(2):457-71.
25. Valenti R, Huber V, Filipazzi P, et al. Human tumor-released microvesicles promote the differenti-
ation of myeloid cells with transforming growth factor-beta-mediated suppressive activity on T
lymphocytes. Cancer Res 2006;66(18):9290-8.
26. Ostrand-Rosenberg S, Sinha P. Myeloid-derived suppressor cells: linking inflammation and
cancer. J Immunol 2009;182(8):4499-506.
27. Shurin GV, Ouellette CE, Shurin MR. Regulatory dendritic cells in the tumor immunoenviron-
ment. Cancer Immunol Immunother 2012;61(2):223-30.
28. Kalinski P. Regulation of immune responses by prostaglandin E2. J Immunol 2012;188(1):21-8.
29. Viola A, Sarukhan A, Bronte V, Molon B. The pros and cons of chemokines in tumor immuno-
logy. Trends Immunol 2012 ;33(10) :496-504.
30. Sawanobori Y, Ueha S, Kurachi M, et al. Chemokine-mediated rapid turnover of myeloid-
derived suppressor cells in tumor-bearing mice. Blood 2008;111(12):5457-66.
31. Molon B, Ugel S, Del Pozzo F, et al. Chemokine nitration prevents intratumoral infiltration of
antigen-specific T cells. J Exp Med 2011;208(10):1949-62.
32. Ko JS, Rayman P, Ireland J, et al. Direct and differential suppression of myeloid-derived suppres-
sor cell subsets by sunitinib is compartmentally constrained. Cancer Res 2010;70(9):3526-36.
33. Jenkins SJ, Ruckerl D, Cook PC, et al. Local macrophage proliferation, rather than recruitment
from the blood, is a signature of TH2 inflammation. Science 2011;332(6035):1284-8.
34. Aziz A, Soucie E, Sarrazin S, et al. MafB/c-Maf deficiency enables self-renewal of differentiated
functional macrophages. Science 2009;326(5954):867-71.
35. Kuang D-M, Wu Y, Chen N, et al. Tumor-derived hyaluronan induces formation of immunosup-
pressive macrophages through transient early activation of monocytes. Blood
2007;110(2):587-95.
36. Egeblad M, Ewald AJ, Askautrud HA, et al. Visualizing stromal cell dynamics in different tumor
microenvironments by spinning disk confocal microscopy. Dis Model Mech
2008;1(2-3):155-67-discussion165.
37. Van Ginderachter JA, Movahedi K, Van den Bossche J, et al. Macrophages, PPARs, and cancer.
PPAR Res 2008;2008:169414.
38. Banerjee S, Lin C-FL, Skinner KA, et al. Heat shock protein 27 differentiates tolerogenic macro-
phages that may support human breast cancer progression. Cancer Res 2011;71(2):318-27.
39. Shirota Y, Shirota H, Klinman DM. Intratumoral injection of CpG oligonucleotides induces the
differentiation and reduces the immunosuppressive activity of myeloid-derived suppressor cells.
J Immunol 2012;188(4):1592-9.
40. Nonaka M, Ma BY, Imaeda H, et al. Dendritic cell-specific intercellular adhesion molecule
3-grabbing non-integrin (DC-SIGN) recognizes a novel ligand, Mac-2-binding protein, characte-
ristically expressed on human colorectal carcinomas. J Biol Chem 2011;286(25):22403-13.
41. Scarlett UK, Rutkowski MR, Rauwerdink AM, et al. Ovarian cancer progression is controlled by
phenotypic changes in dendritic cells. J Exp Med 2012;209(3):495-506.
42. Geissmann F, Manz MG, Jung S, et al. Development of monocytes, macrophages and dendritic
cells. Science 2010;327(5966):656-61.
43. Schulz C, Gomez Perdiguero E, Chorro L, et al. A lineage of myeloid cells independent of Myb
and hematopoietic stem cells. Science 2012;336(6077):86-90.
Ontvangen: 15/01/2013 Aanvaard: 13/05/2013