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Molecular and functional heterogeneity of meyloid cells in cancer

woensdag, 29 september, 2010 - 11:00
Campus: Brussels Humanities, Sciences & Engineering campus
Faculteit: Science and Bio-engineering Sciences
Kiavash Movahedi
doctoraatsverdediging

Myeloid cells play an important role during tumor progression. A systemic expansion of
these cells in tumor-distal organs such as the spleen, and a high infiltration in the tumormicroenvironment
indicate an involvement at different levels. However, myeloid cells are
highly heterogeneous, and because of this heterogeneity many of their specific properties
in cancer settings remain ill-defined. This work aimed to further characterize myeloid cells
in cancer, in an attempt to deepen the biological understanding of these cells and
potentially provide new therapeutic opportunities. More specifically, we focused on (i)
Myeloid-Derived Suppressor Cells, an immunosuppressive population that expands in
secondary lymphoid organs of tumor bearing hosts and (ii) Tumor-Associated
Macrophages, which are a major component of the tumor microenvironment.

The induction of CD11b(+)Gr-1(+) myeloid-derived suppressor cells (MDSCs) is an
important immune-evading mechanism used by tumors. However, the exact nature and
function of MDSCs remained elusive, especially because they constitute a heterogeneous
population that had not yet been clearly defined. In this work, we identified 2 distinct
MDSC subfractions with clear morphologic, molecular, and functional differences. These
fractions consisted of either mononuclear cells (MO-MDSCs), resembling inflammatory
monocytes, or low-density polymorphonuclear cells (PMN-MDSCs), akin to immature
neutrophils. Interestingly, both MO-MDSCs and PMN-MDSCs suppressed antigen-specific Tcell
responses, albeit using distinct effector molecules and signaling pathways. Blocking
IFN-gamma or disrupting STAT1 partially impaired suppression by MO-MDSCs, for which
nitric oxide (NO) was one of the mediators. In contrast, while IFN-gamma was strictly
required for the suppressor function of PMN-MDSCs, this did not rely on STAT1 signaling or
NO production. Finally, MO-MDSCs were shown to be potential precursors of highly
antiproliferative NO-producing mature macrophages. However, distinct tumors
differentially regulated this inherent MO-MDSC differentiation program, indicating that this
phenomenon was tumor driven. Overall, these data refine tumor-induced MDSC functions
by uncovering mechanistically distinct MDSC subpopulations, potentially relevant for
MDSC-targeted therapies.

Tumor-associated macrophages (TAMs) form a major component of the tumor stroma.
However, important concepts such as TAM heterogeneity and the nature of the monocytic
TAM precursors remained speculative. This work now shows for the first time that mouse
mammary tumors contained functionally distinct subsets of TAMs and provides markers for
their identification. Furthermore, in search of the TAM progenitors, we show that the
tumor-monocyte pool almost exclusively consisted of Ly6C(hi)CX3CR1(low) monocytes,
which continuously seeded tumors and renewed all nonproliferating TAM subsets.
Interestingly, gene and protein profiling indicated that distinct TAM populations differed at
the molecular level and could be classified based on the classic (M1) versus alternative
(M2) macrophage activation paradigm. Importantly, the more M2-like TAMs were enriched
in hypoxic tumor areas, had a superior proangiogenic activity in vivo, and increased in
numbers as tumors progressed. Finally, it was shown that the TAM subsets were poor
antigen presenters, but could suppress T-cell activation, albeit by using different
suppressive mechanisms. Together, these data help to unravel the complexities of the
tumor-infiltrating myeloid cell compartment and provide a rationale for targeting
specialized TAM subsets, thereby optimally "re-educating" the TAM compartment.

Our results also show that the Macrophage Mannose Receptor (MMR), an endocytic
membrane molecule, was expressed on TAMs but not on other cell types present in the
tumor. Furthermore, the M2-like TAMs expressed the highest levels of MMR, suggesting
that this is a marker that can potentially be used for the in vivo targeting of this cell
population. Therefore, we have now created camelid heavy-chain antibody fragments or
"nanobodies" raised against the MMR and show that these nanobodies efficiently bind to
TAMs ex vivo. In addition, our results show that anti-MMR nanobodies can be used for the
in vivo imaging of MMR+ cells in solid tumors using pinhole SPECT/micro-CT imaging.

Finally, our work emphasizes that monocytes play a primordial role in tumor-bearing
hosts, be it as MDSCs in the spleen/circulation or as progenitors of TAMs in the tumor. A
more thorough understanding of monocyte activation and function, especially in tumor
settings, therefore remains important. However, the lack of a straightforward and reliable
method for the isolation of mouse blood monocytes remains a hurdle. We now describe a
fast and easy method for isolating monocytes from mouse blood based on immunomagnetic
labeling.

In conclusion, this work brings new insights in the biology of myeloid cells in cancer,
highlighting the existence of molecularly and functionally distinct subsets of MDSCs and
TAMs and potentially being relevant for future therapeutic interventions.

Bijlage: 
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