Cancer Immune Therapy Edited by G. Stuhler and P. Walden ...

Abnormalities in monocyte function have been described in cancer. Consistent with
this, some investigators [72±75] have reported difficulties in generating [76] monocyte-derived
DCs (Mo-DCs) in cancer patients, whereas others have not [73]. Cancers
may also influence DC production at an even earlier level and vascular endothelial
growth factor (VEGF) has been suggested to suppress DC production in the bone
marrow [77].
Thus, the data to date suggests that cancers fail to activate DCs sufficiently and,
furthermore, that they liberate a variety of mediators, which compromise DC function.
Thus, there appears to be a clear defect in the immune response to cancer,
which is an opportunity to be tested for remedial action.
9.4
Blood DC Counts and DC Mobilization
9.4 Blood DC Counts and DC Mobilization
The ability to count DCs in the blood and to monitor them in the tissues is fundamental
to studying DC biology in cancer. It is also a pre-requisite to plan DC mobilization
and therapeutic procedures. Fortunately, modern flow cytometry techniques
allow this relatively rare cell to be tracked in the blood [78, 79]. Most laboratories prepare
human blood DC using a mixture of monoclonal antibodies (mAbs) to lineage
antigens (the choice is critical) and then a variety of immunoselection procedures to
remove these cells prior to further analysis or use them in functional assays. How
the cells are prepared and just what subsets of blood DCs are present is being redefined
at present as a result of recent studies ([20] and MacDonald et al., submitted).
Whilst it is still convenient to describe a CD11c + (CD123 lo ) myeloid subset and
CD11c ± CD123 hi lymphoid subset, it is clear that other (perhaps even functionally
distinct) myeloid subsets can be defined (MacDonald et al., submitted). Laboratories,
used to counting rare cell populations, are now starting to analyze blood DCs in
whole blood or in peripheral blood mononuclear cell (PBMC) populations.
Blood DCs represent (depending on the phenotypic definition) 0.5±1.5% of PBMCs.
A range of 0.15±0.70% or 3±17 × 10 6 DC/l was obtained using the mAb CMRF-44
[79]. Studies on patients undergoing surgery showed an acute rise in absolute blood
DC counts, which peaked before monocytes [80]. Interestingly, blood DC counts are
not increased in patients with chronic myelomonocytic leukemia [81].
Blood DC counts have been studied following hematopoietic stem cell mobilization
for autologous and allogeneic stem cell transplants [79]. In normals, granulocyte
colony stimulating cell (G-CSF) mobilization appears to increase CD123 + DC
counts selectively over the CD11c population [82]. This effect is less obvious in cyclophosphamide/G-CSF
mobilized patients with multiple myeloma and low-grade
non-Hodgkin's lymphoma (NHL) (Vuckovic et al., submitted) and patients who
have received chronic myelosuppressive chemotherapy, patients may have lower
numbers of circulating DCs. Flt-3 ligand (Flt-3L) and Flt-3L/G-CSF have now been
used to mobilize blood DCs. Myeloid DCs counts increase approximately 40-fold
with a 10-fold increase in the lymphoid subset in normal individuals [83] and increases
are reported in cancer patients [84, 85]. Nonetheless, DCs may mobilize
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