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

102 6 Immune Cells in the Tumor Microenvironment
which enable them to survey the target for the presence of class I MHC molecules
[40]. These receptors are of two types: killer inhibitory receptors (KIRs) and killer activating
receptors (KARs) [41, 42]. NK cell functions and their interactions with other
cells or the extracellular matrix (ECM) molecules are regulated through these receptors
and Fcg receptors (FcgRs).
NK cells are strategically distributed throughout body fluids and tissues. Studies of
NK cell localization in human tissues have been difficult, however, because immunostaining
for NK cells has not been reliable. The anti-NK cell antibodies which
work well in flow cytometry are not useful for phenotyping in tissues, especially in
paraffin-embedded human specimens [43]. Antibodies specific for perforin or granzymes
are more reliable immunostaining reagents, with a caveat that activated cells
other than NK cells may be enriched in granules containing these components.
Therefore, much of the information about NK cell distribution in human tissues, including
tumors, is derived from studies performed with freshly isolated NK cells
using flow cytometry for phenotyping and 51 Cr-release assays with K562 as targets,
which measure the capability of these effector cells to induce secretory or necrotic
killing [37]. Tissues that are known to contain the largest proportions of activated NK
cells include the liver, lungs and the placenta during pregnancy [36, 43]. Lymphocytic
infiltrates associated with infections in these organs contain numerous activated NK
cells [44]. Importantly, however, hepatocellular carcinomas, colon tumors metastatic
to liver, lung cancers or ovarian carcinomas are not found to be enriched in NK cells
[43]. In general, few NK cells have been observed in lymphocytic infiltrates of human
solid tumors and particularly of advanced lesions, although they may be a more prominent
component of early lesions or tumors associated with viral infections, such
as the cervical carcinoma [18, 36]. The presence of NK cells in inflammatory but not
neoplastic conditions suggests either that their primary biologic role is elimination
of infectious targets rather than tumor cells [45] or that the tumor microenvironment
preferentially induces their demise. The available evidence appears to point to the
latter possibility. Indeed, it has been observed that NK cells purified from ascites of
women with ovarian carcinoma have profoundly depressed responses to IL-2
(Fig. 6.4) [46] and express low levels of message for IFN-_ but significantly increased
levels of mRNA for IL-10 compared to normal circulating NK cells (Fig. 6.5). Furthermore,
relative to normal NK cells, decreased or absent expression of the z chain, associated
in NK cells with FcgRIII, was observed in NK cells obtained from ovarian ascites
as well as in circulating NK cells of patients with several types of cancer, including
melanoma (Fig. 6.6). Our recent studies suggest that among circulating NK cells
in patients with breast cancer, a subset of CD56 bright CD16 dim NK cells, which represents
about 95% of all NK cells and is responsible for effector functions, preferentially
binds Annexin V and thus is primed for apoptosis (unpublished data). These
patients also had significantly lower NK activity than the age- and sex-matched
healthy controls tested in parallel, an indication that Annexin-binding NK cells were
indeed functionally impaired. These and other recent observations suggest that endogenous
circulating or tissue-resident NK cells have the potential to play a role in
tumor surveillance and control of metastasis dissemination. However, once the tumor
is established, it might subvert anti-tumor functions of NK cells, especially in