The Presence of NK Cells Inside Tumors

One of the major difficulties in the detection of NK cells in tumors is the lack of a single NK specific marker. The classical NK marker in human (CD56) is expressed also on NKT cells, and is absent in mice. To identify NK cells in the mouse the DX5 or NK1.1 mAb are used and these two receptors are also not specific to NK cells only, or are expressed only in certain mouse strains [4]. The only NK specific marker known to date is the NKp46 in human, or NCR1 in mouse. Indeed, NK cells were recently identified in Renal-Cell-Carcinoma patients by using antibodies against the NKp46 receptor [14]. Developing additional antibodies to the human NKp46 and the mice NCR1 will facilitate easier detection of NK cells in the future. Several studies reported on the presence and functions of NK in tumors [15]. For example, intratumor NK cells were found in squamous cell lung cancer, gastric and colorectal carcinomas [16-18] and these studies suggested that the presence of NK cells inside the tumor is an indicative for a good prognosis. NK cells derived from malignant biopsies of ductal invasive breast cancer had enhanced IFNg and IL-4 production [19]. In addition, NK cells were demonstrated to specifically infiltrate tumors metastasis tissue after IL-2 treatment [20]. However, in this case, the in situ detection of NK cells was performed by using CD56 only (which also detect NKT cells). In mouse model of B16 melanoma metastases in the lung, NK cells were identified with anti-asialo GM1, and increased NK numbers were demonstrated after IL-2 treatment [21].

While NK cells are considered to provide a first line of innate defense against any transformed cells, the question of whether they are present at the initial site of the pre-cancerous stages is still unknown. In addition, the emerging concept of epithelial-mesenchymal transition (EMT) [15] was not investigated with regard to NK surveillance. In this concept, while primary carcinoma cells might be less accessible behind the basement membrane, they also possess a less dangerous treat. Once cells go through the EMT and become invasive and consequently more dangerous, they are also more exposed to NK cell attack [15]. It will be interesting to characterize whether NK cells will better-recognize such EMT-phenotype cancer cells, which represent a more dangerous stage of tumor progression. In addition, invasive edge of carcinomas and the outermost cells of tumors which are accessible to NK-recognition are preferentially at EMT condition [15]. Finally, tumor cells were demonstrated to revert from this EMT phenotype after establishment of metastases due to their new stromal environment [15]. This phenotypic change enables further growth, and according to the above hypothesis might also decrease the in vivo sensitivity to NK attack. Thus the tumor microenvironment influences the tumor cell phenotype and might also determine tumor susceptibility to NK cell killing.

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