Page 14 - TD-1-1

Tumor Discovery Monocytes from single-cell analysis

CD117, C-type lectin CLEC12A and CD64. Besides, in explained by polarization theory. M2 macrophages are
contrast to mouse cMoPs, human cMoPs express CD135, a classified into four subsets and are activated through
cytokine receptor and early hematopoietic marker . different mechanisms. On the other side, another report
[55]
Using single-cell transcriptome profiling on the may contradict previous findings. Franklin et al. found
re-granulocyte-macrophage progenitor (pre-GM), that RBPJ (an important transcriptional regulator of
Drissen et al. identified different differentiation pathways the Notch signaling pathway) was fundamental for the
[64]
of myeloid cells . To be specific, they found that mast differentiation of inflammatory monocytes into TAM .
[56]
cells, eosinophils, megakaryocytes, and erythroid cells are TAMs are phenotypically and functionally different from
hi
hi
generated through a pathway expressing the gene encoding the traditional M2 TAMs (defined as MHCII CD11b
the transcription factor GATA-1, while monocytes along cells) in the mouse model of mammary cancer. This is
with neutrophils and lymphocytes are generated through unexpected because IL-4 produced by other immune cells
a pathway lacking expression of that gene. This indicates a in the TME is thought to be fundamental for polarization
−/−
[65]
-
new pattern of an early hematopoietic-lineage bifurcation into M2 . In addition, they found that IL4 MMTVPyMT
that separates the myeloid lineages. mouse model of mammary tumor had normal proportions
of CD11b Vcam1 TAMs. Taken together, these results
+
lo
CSF-1 tightly correlates with tissue morphogenesis . indicate that TAMs might not be M2 and not be generated
[57]
Soluble CSF-1 in TME makes macrophages trophic to tumor secondary to the adaptive immune response against tumors.
cells, and CSF-1 and interleukin (IL)-6 impede the maturation
of DCs together. CSF-1 expressed on the surface of tumor In addition, contrary to our traditional knowledge about
cells along with IL-4, IL-12, IL-13, and GM-CSF promotes polarized macrophage subsets, a recent study has found
maturation of DCs. IL-4, IL-10, IL-13, and other cytokines in that macrophages, which were generated from monocytes
+
the TME can activate TAMs and promote different immune in vitro and underwent classical (LPS IFN-γ) or alternative
responses . Taken together, the molecular cytokines in the (IL-4) activation, are not equivalent to M1 and M2
[58]
microenvironment fundamentally dictate whether TAMs macrophages, respectively. The discrepancy might explain
promote or inhibit tumor progression . M1 macrophages why most surface markers identified on macrophages in
[3]
can be activated in response to microbial products, interferon vitro do not translate into in vivo situations. Hence, more
[66]
gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), and valid markers of in vivo M1/M2 are needed .
GM-CSF, followed by activation of Toll-like receptor signaling The reason that monocytes preferentially
pathways . A single-cell transcriptomic study that analyzed differentiate into immunosuppressive TAMs rather than
[39]
DCs and monocytes of 333 individuals suffering from single immunostimulatory DCs is a subject of investigation.
lymph node melanoma metastasis revealed that IFN-γ signature The unclear mechanisms underlying the preferential
and 227-gene signature are highly positively correlated. They differentiation pathway have become a barrier for
also found that different immune mononuclear phagocytes immunotherapies, especially in solid tumor treatment.
shared a conserved steady-state program during differentiation Retinoic acid (RA) has been identified as a signal that induces
and entry into healthy tissue . tissue-specific localization and functional polarization of
[59]
Cytokines including IL-4, IL-13, IL-10, IL-33, and IL-21, peritoneal macrophages through the reversible induction
[67]
transforming growth factor beta (TGF-β), M-CSF/CSF-1, of transcription factor GATA6 . In 2016, a study showed
and glucocorticoids induce M2 activation programs [4,39,60] . that an in vitro treatment of sarcoma-bearing mice with
Michielon et al. had established an in vitro three- all-trans RA (ATRA) eliminated monocytic MDSCs and
dimensional (3D) organotypic human melanoma-in-skin dampened the immune-suppressive role of MDSCs. This
model and revealed that IL-10 is partly responsible for the indicates that ATRA synergizing with disialoganglioside-
transformation of monocytes into M2-like macrophages chimeric antigen receptor (CAR) T cells would be more
[60]
(defined as CD163 PD-L1 ) . Furthermore, monocytes effective in fighting against sarcoma xenografts . In 2020,
+
+ [61]
orchestrated GM-CSF and IL-4 stimulation, resulting in Devalaraja et al. revealed that TME induced tumor cells to
a mode- and time-dependent differentiation relying on secrete RA, which skews monocyte differentiation toward
nuclear receptor corepressor 2 (NCOR2), a transcriptional macrophages rather than DCs. This also highlights the
regulator . IL-1β also regulates the TAM/macrophage potential of the combination of RA signaling blockade and
[62]
[68]
polarization by regulating expression of intercellular anti-PD-1 therapy in enhancing the treatment efficacy .
adhesion molecule 1 (ICAM-1) and vascular cell adhesion The verification of some of the above-mentioned
molecule 1 (VCAM-1) in glioblastoma . mechanisms by single-cell analysis yielded new findings to
[63]
As mentioned previously, macrophages undergo a help with our understanding of the origin, function and
continuum of functional states that cannot be simply related signaling pathways for differentiation of TAMs

Volume 1 Issue 1 (2022) 5 https://doi.org/10.36922/td.v1i1.4