Avid Bioservices Inc (CDMO)

[freethemice]

This is an interesting paper on pancreatic cancer.
My interest here is the MOA for bavituximab proposed by Dr. Thorpe which involves the switching of
macrophage phenotypes from the immunosuppressive M2-type to the immunostimulatory M1-type.
This paper shows how pancreatic patients with more M2-type have a higher survival than the patients with
more of the M2-type. If this MOA is valid then we might also expect it would be also true in NSCLC.

Significance of M2-Polarized Tumor-Associated Macrophage in Pancreatic Cancer
Journal of Surgical Research 167, e211–e219 (2011)
http://www.sciencedirect.com/science/article/pii/S0022480409002844
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Background. The roles of infiltrating macrophages
within the tumor microenvironment are complex
because of their functional variety. The aim of this
study is to examine the role and prognostic significance
of tumor-associated macrophages (TAMs) that
have an M2 polarized function in pancreatic cancer.
Materials and Methods. Formalin-fixed, paraffinembedded
blocks were obtained from 76 patients
with pancreatic head cancer. All patients underwent
macroscopic curative resection. We assessed the number
of infiltrating macrophages within the tumor invasive
front by not only CD68 but also by CD163 and
CD204, which are specific receptors on M2-polarized
macrophages. Furthermore, to evaluate lymphangiogenesis,
we measured the density of lymphatic vessels
in the tumor invasive front by using D2-40.
Results. High incidence of lymph node metastasis
was shown in cases with a high number of CD163- or
CD204-positive macrophages. Significantly increased
lymphatic vessel density (LVD) was shown in cases
with lymph node metastasis compared with cases without
lymph node metastasis (P[0.0094). Significantly
increased LVD (P[0.0175) and a poor prognosis
(P[0.0171) were shown in cases with a high number
of macrophages that express CD163 or CD204, however,
there was no significant difference according to
the number of CD68-positive macrophages.
Conclusions. M2-polarized TAMs in the invasive
front of pancreatic cancer are associated with a poor
prognosis due to accelerated lymphatic metastasis
and inhibition of the functional interaction between
M2-polarized TAMs and tumor cells may improve the
prognosis
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Note that this figure shows the markers low CD163/CD204 (M1-type macrophages) have a
significantly better survival then the high CD163/CD204 (M2-type macrophages).
In fact, the figure B shows that the MOS for the M2 type is approximately 9 months and the MOS
for the patients with predominately M1 type is approximately 18 months, or a doubling of MOS.
It also shows that using high and low CD68 as a marker does not work as well.

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INTRODUCTION
Pancreatic cancer is more aggressive than any other
gastrointestinal malignancy due to the propensity for
hematogenous or lymphatic metastasis in its early
stage, which is associated with a poor prognosis [1].
Compelling evidence has emerged in recent years that
the tumor microenvironment plays a critical role in
tumor progression [2, 3]. Solid tumors are comprised of
tumor and nontumor cells, such as resident stromal cells
and migratory hemopoietic cells. Complex crosstalk between
these cells regulates tumor growth, invasion, and
metastasis. Macrophages are one of the major components
of the tumor microenvironment; those are derived
from CD34þ bone marrow progenitors develop into
monocytes, and extravasate into various tissues where
they differentiate into resident macrophages. Macrophages
are a heterogeneous cell population that adapt
and respond to a large variety of microenvironmental
signals. While macrophage activation by T helper 1
(Th1) cytokines, such as interferon-g (IFN- g), interleukin-
1b (IL- b), and lipopolysaccharide was named ‘‘classical’’
activation, that byThelper 2 (Th2) cytokines, such
as IL-4 and IL-13 was named ‘‘alternative’’ activation.
Mirroring the Th1 and Th2 nomenclature, many
researchers refer to polarized macrophages as M1 and
M2 cells [3]. These subpopulations of macrophage have
different types of receptor expression and cytokine and
chemokine production. M1-polarized macrophages
have the IL-12high, IL-23high, IL-10low phenotype and
produce tumor necrosis factor a (TNF-a) and nitric oxide
(NO): M1-polarized macrophages are potent effector
cells that kill microorganisms and tumor cells. In contrast,
M2-polarized macrophages have the IL-12low,
IL-23low, IL-10high phenotype and have high expression
of several receptors, such as class A scavenger receptor
(SR-A, CD204) and mannose receptor (MR, CD163).
M2-polarized macrophages scavenge debris and
promote angiogenesis, tissue remodeling, and repair
[3, 5]. Circulating monocytes were shown to be recruited
by chemotactic factors produced by tumor cells into the
tumor microenvironment and differentiated to tumorassociated
macrophages (TAMs), which have the polarized
M2 phenotype [5, 6]. TAMs receive signals from
diverse cells within the tumor microenvironment and
release various growth factors and cytokines and promote
tumor cell invasion, induce angiogenesis, suppress
antitumor immunity, and facilitate tumor cell metastasis [3–6].
[snip]

DISCUSSION
A dense, desmoplastic stroma rich in inflammatory
cells, fibroblasts, and extracellular matrix proteins is
a trait of pancreatic cancer [36]. TAMs are important
components of inflammatory cells. Macrophages are
plastic cells: they can switch from an activated M1 state
back to M2, and vice versa, according to specific signals.
Malignant tumors recruit circulating monocytes/macrophages
into their microenvironment and let them
mature and differentiate into TAMs that have the M2
phenotype [3–5]. In this tumor microenvironment,
paracrine interaction between cancer cells and TAMs
promotes tumor invasion, angiogenesis, and metastasis.
[snip]
In conclusion, M2-polarized TAMs in the invasive
front of pancreatic cancer promote lymphangiogenesis,
facilitate lymphatic metastasis, and could be a predictor
of a poor prognosis. It is possible that therapy
aimed at disrupting the functional interactions
between pancreatic cancers cells and infiltrating M2-
polarized macrophages may decrease lymphatic
metastasis and prolong survival.