Cellular immune suppression in cancer patients and its implication for dendritic cell therapy. Sub-category: Cell-Based Therapy

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Author(s): J. Nesselhut,
D. R. Lorenzen, D. Marx, R. Y. Chang, C. Matthes, B. Hildenbrand, E. M.
Schneider, T. Nesselhut; Institute for Tumor Therapy, Duderstadt,
Germany; Meridian Medical Group, New York, NY; Clinic for Tumor
Biology, Freiburg, Germany; University Hospital Ulm, Ulm, Germany
Background: The
treatment of human cancer with monocyte-derived dendritic cells (MoDC)
is a promising and innovative approach. However, many of the treated
patients fail to respond to therapy. The reduced clinical antitumor
response may be due to an inflammatory immune-suppressive tumor
microenvironment. Regulatory T-cells (T-reg) and other cells with
suppressive potential can promote an immune suppressive tumor
microenvironment and thus play an important role in regulation of the
immune response.
Methods: Whole blood from n=100 cancer
patients with various tumor types and from n=30 healthy donors were
analysed by flow cytometry. CD4+ lymphocytes with immune suppressive potential were characterized by analysing the expression of CD25, CD39, CD127.
Results: We found a significantly higher proportion of CD25+/CD39+ and of CD25+/CD127low
T-helper cells in the blood of cancer patients as compared to healthy
donors. This may indicate two different types of T-reg involved in
immune suppression in cancer patients. Treatment of patients with
metronomic chemotherapy induced a down-regulation of these cells.
Interestingly, we found a subpopulation of cells within the lymphocyte
gate characterized by CD2high and CD86 expression in cancer
patients with very advanced stage, similar to such normally found in
hemaphagocytic lymphohistiocytosis (HLH) patients characterized by
exceeding high plasma concentration of IFN-g and IL-10 (Schneider et
al. 2002). These cells can be down-regulated by treatment with a
tetradecapeptide (Ezrin) known to act as an immune modulator with
anti-viral activity leading to reduction of inflammatory cytokines.
An efficient induction of a clinical antitumor response requires both a
polarization of MoDC in a TH1 direction as well as changing an immune
suppressive tumor microenvironment. For the first time, we identified
HLH associated cells in advanced cancer patients. As HLH is
characterized by hyperinflammation, these cells may indicate an
inflammatory tumor microenvironment. Thus, anti-inflammatory therapy
should be considered as co-treatment with immunotherapy with dendritic
cells for down-regulation of immune suppressive cells (T-reg, CD2high/CD86+ cells) to promote a clinical antitumor response.