C. Menetrier-caux et al., Renal cell carcinoma induces interleukin 10 and prostaglandin E-2 production by monocytes, BR J CANC, 79(1), 1999, pp. 119-130
Immunotherapy with interleukin 2 (IL-2) is not an effective anti-cancer tre
atment in the majority of patients with renal cell carcinoma (RCC), suggest
ing that the activation of cytotoxic T cells or NK cells may be impaired in
vivo in these patients. The production of immunosuppressive factors by RCC
was investigated. Using immunohistochemistry, IL-10 was detectable in 10 o
f 21 tumour samples tested. IL-10 was undetectable in the supernatant of ce
ll lines derived from these RCCs. However, these cell lines or their condit
ioned medium (RCC CM), but not normal renal epithelial cells adjacent to th
e RCC or breast carcinoma cell lines, were found to induce IL-10, as well a
s prostaglandin E-2 (PGE(2)) and tumour necrosis factor (TNF)alpha producti
on by autologous or allogeneic peripheral blood mononuclear cells (PBMCs) a
nd monocytes. IL-10 production induced by RCC CM was found to be dependent
on TNF-alpha and PGE(2) since an anti-TNF-alpha antibody (Ab) inhibited 40-
70% of IL-10 production by monocytes, and the combination of anti-TNF-alpha
Ab and indomethacin, an inhibitor of PGE(2) production, inhibited 80-94% o
f RCC CM-induced IL-10 production by monocytes. The RCC CM of the five cell
lines tested were found to induce a down-regulation of the expression of H
LA-DR and CD86, as well as a strong inhibition of mannose receptor-dependen
t endocytosis by monocytes. The blockade of HLA-DR and CD86 expression was
partially abrogated by indomethacin and anti-IL-10 Ab respectively, and com
pletely abrogated by an anti-TNF-alpha Ab. The inhibition of mannose recept
or-dependent endocytosis was partially abrogated by an anti-IL-10 Ab and co
mpletely abrogated by an anti-TNF-alpha Ab. These results indicate that RCC
s induce IL-10, PGE(2) and TNF-alpha production by monocytes, which down-re
gulate the expression of cell-surface molecules involved in antigen present
ation as well as their endocytic capacity.