Professional Documents
Culture Documents
Introduction
As cancer represents a very diverse biology depending
on the genetic background, the organ of origin and
confounding factors it remains ambitious to dissect this
complex cellular microenvironment into its main
driving factors. Among these factors an important role
has been attributed to both the adaptive and innate
immunity. For a long time, the immune regulatory
capacity (e.g. regulatory T cells) of the adaptive
immune system was a major focus of research
concerning the involvement of immune cells in the
tumor microenvironment with only few reports
published on its role in tumor growth promotion and
metastasis.
In contrast terms such as angiogenesis, tumor growth or
metastasis have been attributed to cells of innate
immune origin (Hicks et al., 2006). The innate immune
system is represented by different cell subsets including
natural killer (NK) cells, dendritic cells (DC),
neutrophils, and macrophages (M). Tumor-associated
macrophages (TAMs) constitute a major part of the
leukocytic infiltrate in human cancer and the amount of
tumor infiltrating macrophages has early been
associated with clinical outcome (Mantovani et al.,
2008; Pollard, 2009). When assessing studies that
identified TAMs simply as CD68+ cells it is
challenging to assign a strict pro- or anti-tumorous
function to the TAM infiltrate. Nevertheless,
macrophage infiltration is associated with poor
prognosis in breast cancer (Finak et al., 2008; Beck et
al., 2009), Hodgkin's lymphoma (Steidl et al., 2010), Tcell lymphoma (Niino et al., 2010), cervical cancer
765
molecularly
characterize
small
numbers
of
macrophages from human tumor specimens (Clark et
al., 2007).
766
Pro-inflammatory and
properties of TAMs
growth
promoting
767
768
Figure 1: Induction of TAMs in the tumor microenvironment. Circulating monocytes are recruited into the tumor by growth factors
and chemokines. Local presence of M-CSF causes the differentiation of monocytes to macrophages. Soluble tumor derived factors
initiate the polarization of macrophages into TAMs leading to the expression of molecules that support angiogenesis, tumor growth and
metastasis. Conversely TAMs secrete factors that induce local immune suppression by recruitment of Treg cells or suppress T cell
responses directly.
769
Re-Polarization of TAMs
The plastic nature of macrophages allows to re-polarize
them into a more tumoricidal phenotype than the tumor
associated phenotype, for example the proinflammatory M1-like phenotype. Reversion of the
tumor-associated M2-like status into a M1-like
phenotype has been shown to improve anti-tumor
responses. Especially IFNg, nitric oxide and IL-12
produced by macrophages or expressed exogenously
repress tumor cell growth (Lewis and Pollard, 2006;
Peron et al., 2004). In general, this can be
accomplished by different methods. A combination of
chemotherapy with vincristine, cyclophosphamide and
doxorubicin together with immunotherapy with CpGODN led to a shift in the TAM population from a rather
M2-like towards a M1-like phenotype with
upregulation of MHC II, IFN-, TNF- and IL-12
(Buhtoiarov et al., 2011). Zoledronic acid, besides its
macrophage depleting effect, has been shown to reduce
VEGF expression in TAMs as well as to induce
expression of iNOS, one of the hallmark genes of M1like polarization (Coscia et al., 2010). The histidinerich glycoprotein (HRG) skews TAM polarization
away from the M2-like to a M1-like phenotype and
suppresses placental like growth factor (PLGF) (Rolny
et al., 2011; Huang et al., 2011). Inhibition of PGE2
production in tumor cells by COX inhibitors and
blocking of IL-6 can prevent differentiation of
monocytes into M2-like macrophages in the tumor
microenvironment (Heusinkveld et al., 2011).
Interaction of already polarized M2-like macrophages
with Th1 cells results in a repolarization of M2-like
into M1-like macrophages with induction of
costimulatory molecules and production of IL-12.
Similar effects could be observed by stimulating M2like cells with CD40L+ cells and IFN- (Heusinkveld et
al., 2011).
References
Osborne J, Moore PS, Chang Y. KSHV-encoded viral IL-6
activates multiple human IL-6 signaling pathways. Hum
Immunol. 1999 Oct;60(10):921-7
Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000
Jan 7;100(1):57-70
770
Lake RA, van der Most RG. A better way for a cancer cell to
die. N Engl J Med. 2006 Jun 8;354(23):2503-4
771
Roland CL, Dineen SP, Lynn KD, Sullivan LA, Dellinger MT,
Sadegh L, Sullivan JP, Shames DS, Brekken RA. Inhibition of
vascular endothelial growth factor reduces angiogenesis and
modulates immune cell infiltration of orthotopic breast cancer
xenografts. Mol Cancer Ther. 2009 Jul;8(7):1761-71
772
Zhang W, Zhu XD, Sun HC, Xiong YQ, Zhuang PY, Xu HX,
Kong LQ, Wang L, Wu WZ, Tang ZY. Depletion of tumorassociated macrophages enhances the effect of sorafenib in
metastatic liver cancer models by antimetastatic and
antiangiogenic effects. Clin Cancer Res. 2010 Jul
1;16(13):3420-30
Zhou Q, Peng RQ, Wu XJ, Xia Q, Hou JH, Ding Y, Zhou QM,
Zhang X, Pang ZZ, Wan DS, Zeng YX, Zhang XS. The density
of macrophages in the invasive front is inversely correlated to
liver metastasis in colon cancer. J Transl Med. 2010 Feb
8;8:13
limit
773
Zhang BC, Gao J, Wang J, Rao ZG, Wang BC, Gao JF.
Tumor-associated macrophages infiltration is associated with
peritumoral lymphangiogenesis and poor prognosis in lung
adenocarcinoma. Med Oncol. 2011b Dec;28(4):1447-52
774