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

104 6 Immune Cells in the Tumor Microenvironment
Fig. 6.6 Correlations between the percent
of CD3 ± CD56 + NK cells expressing
low z versus mean fluorescence index
(MFI) for z. The percentage of NK cells
with low z expression in the circulation
of 17 patients with melanoma or 15 normal
controls was obtained by taking the
mean of MFI established for all normal
controls ± 2 SD as the cut-off point for
calculating cell frequencies. The correlation
for NK cells was negative (r = 0.92;
p < 0.0001) and the patients had significantly
higher percentages of NK cells
with low ñ than normal controls. Reproduced
with permission from Dworacki
et al. [98]. © AACR.
the subsets of NK cells found at the sites of metastasis and those responsible for cytotoxic
functions.
NK cells constitutively express IL-2 receptor and are able to rapidly respond to IL-2
stimulation [47]. Subsets of IL-2-activated NK cells such as A-NK cells, for example,
are potent anti-tumor effector cells which have been used for therapy of cancer in animal
models of tumor growth [48] and in human clinical trials of patients with cancer
[49]. Studies in pre-clinical tumor models in mice suggest that genetically modified
tumors secreting IL-2 become infiltrated by NK cells and rejected, in contrast to
mock-transfected tumors, which harbor few NK cells and grow progressively [50]. In
these experiments performed in nude mice, IL-2 secreted locally by implanted tumor
cells was able to mobilize and activate endogenous NK cells, which in the absence of
T cells were able to induce tumor regression [50]. Although this model of tumor
growth in immunodeficient mice is obviously limited in its therapeutic implications,
it serves to confirm in vitro data, which indicate that IL-2-activated NK cells are potentially
effective in controlling tumor growth, even when T cells are not present. Another
lesson learned from these experiments is that the lack of IL-2 may be a determining
factor in the relative paucity of NK cells in the tumor microenvironment. Indeed,
it has been shown that human tumors are depleted of IL-2 and IFN-g, and this
would make it difficult, if not impossible, to sustain any substantial level of anti-tumor
activity in NK or any other lymphoid cells found at the site [51].