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Page 6 of 14 Diab et al. J Cancer Metastasis Treat 2022;8:42 https://dx.doi.org/10.20517/2394-4722.2022.60

[43]
[43]
stem cell progenitors . Marrow-derived macrophages are recruited into tissues by chemotactic signals .
The origin of TAMs has an implication on their function, as monocyte-derived TAMs have increased
[44]
antigen presentation abilities, while embryonically derived TAMs have profibrotic features . Macrophages
are present in early pancreatic intraepithelial neoplasia (PanIN) lesions and are regarded as one of the
earliest immune responses . Mutation in kras ubiquitously present in these early lesions drives an
[45]
[46]
epithelial-macrophage interplay that promotes a pro-tumorigenic phenotype in the TAMs . Macrophages
in these early PanIN lesions secrete inflammatory factors that facilitate epithelial cell growth . In addition,
[47]
macrophages can serve as sources of IL-6 and IL-10 that activate STAT3 and fuel tumorigenesis through
direct impacts on tumor cells or infiltrating cytotoxic immune cells .
[47]
TAMs have different polarization states within the TME, and their function can be pro-inflammatory/anti-
tumoral (M1 phenotype) or anti-inflammatory/pro-tumoral (M2 phenotype) . M1 TAMs are induced via
[29]
IFNγ and tumor necrosis factor α (TNFα), and they exhibit a high expression of interleukin 12 (IL-12), TNF,
and inducible nitric oxide synthase [29,48] . IFNγ and TNFα are produced by antigen-presenting cells upon
recognition of pathogenic signals, but they are also secreted by T-cells and natural killer (NK) cells [29,48] .
Upon activation, M1 TAMs secrete pro-inflammatory cytokines (e.g., TNFα, IL1β, IL12), effector molecules
(e.g., reactive nitrogen intermediates), and chemokines (e.g., CXCL9, CXCL10) to amplify and sustain their
[42]
tumoricidal activity [29,48] . M2 TAMs are stimulated by interleukin 4 (IL-4) and interleukin 13 (IL-13) . M2
macrophages lose their antigen presentation abilities and function instead to suppress the immune response
through a variety of mechanisms. M1 TAMs reside in the periglandular region close to cancer cells, while
M2 TAMs usually reside more peripherally . Interestingly, when M2 TAMs are observed close to cancer
[6]
cells, they are associated with worse survival . While the M1/M2 classification is a useful and simplified
[6]
approach to understanding the TAM population, it should be noted that TAMs exist in a fluid and dynamic
state, where their polarization is part of the continuous spectrum between M1 and M2 and can change
depending on cytokines and interactions with other cells in the TME .
[48]
Initiatives tailored to TAMs as therapeutic targets have focused on two main concepts, either
reprogramming TAMs to be anti-tumor or retrieving their antigen-presenting abilities. The current review
summarizes some of these initiatives. The colony-stimulating factor 1 (CSF1) polarizes TAMs toward their
[49]
immunosuppressive phenotype via colony-stimulating factor 1 receptor . Research on human and mouse
samples shows that the TME is infiltrated with CSF1R macrophages . Inhibiting CSF1R in KPC mouse
+
[49]
models resulted in an increase in effector T cell infiltrations and decreased tumor burden . Additionally, in
[49]
syngeneic orthotopic mouse models using KC and KI cells, CSF1R blockade sensitizes tumors to immune
checkpoint blockade with PD-1 or CTLA-4 antagonists . Cabiralizumab, a CSF1R blocking antibody, is the
[50]
subject of an ongoing phase 2 clinical trial evaluating its use in combination with nivolumab and
chemotherapy in patients with advanced PDAC .
[51]
The CCL2/CCR2 axis is another pathway that is integral to the genesis of TAMs . Human PDAC cells
[43]
secrete CCL2 that recruits CCR2 monocytes from the bone marrow to the circulation, which then
+
differentiate into TAMs after entering the tumor tissue . In orthotopic mouse models of PDAC (C57BL/6
[43]
and CCR2 mice), blockade of CCR2 results in retention of monocytes in the bone marrow and impaired
-/-
tumor growth . Synergy was observed with the addition of gemcitabine . In an early phase clinical trial,
[43]
[43]
the combination of chemotherapy with a CCR2 inhibitor (PF-04136309) was associated with a reduction in
circulating CCR2 monocytes and TAMs in the tumor and an increase in CD8+ T cells in patients with
+
[52]
PDAC . However, there was a lack of clinical benefit in further trials .
[53]