In the microenvironment of many solid tumors the pH is considerably lo
wer (mean pH between 6.6 to 7.2) than the pH in normal tissue (pH 7.0-
7.5). Therefore, the influence of acidic pH on the cytotoxic activity
of lymphokine-activated killer cells (LAK cells) after different cultu
re periods was tested. K-562 human erythroleukemia cells were selected
as target cells. Cell killing was measured using a two-color flow cyt
ometric method. At physiological pH of 7.4, LAK cell-mediated cytotoxi
city ranged from 15 to 48% (E:T ratio = 50:1). The specific lysis of t
arget cells was considerably reduced (up to 70% inhibition of specific
lysis) under acidic conditions (pH 6.8, 6.3, 5.8). This effect was in
dependent of donors, duration of the culture period, and the E:T ratio
in the cytotoxic assay. As pH gradients surrounding tumor cells may r
each values below pH 6.0 at the cell surface, the pH-dependence of LAK
cell cytotoxicity could at least partially explain the inhibition of
the natural immune response in solid tumors. Therapeutic immunological
strategies concerning the enhancement of the natural immune response
like LAK cell and IL-2 immunotherapy including IL-2 gene therapy may o
nly be successful if a simultaneous inhibition of the acidification pr
ocess and an elevation of tumor pH is achieved.