As expected, the NK cells from intratumoral tissues of advanced-stage HCC exhibited attenuated capacities
for those two cytokine productions. These findings, together with the positive prognostic value of NK cells in the intratumoral region, suggest that infiltration of functional NK cells in HCC tissues may represent the host reaction to malignancy, and, however, that tumor environments administrate NK cell function selleck chemicals llc during disease progression. APCs are critical for initiating and maintaining NK cell responses,23 and Mψ markedly outnumber other APCs in solid tumors.14 We have recently observed that HCC environments can alter the normal developmental process of Mψ that is intended to dynamically regulate monocyte activation in peritumoral stroma, and in that way create conditions that are conducive to tumor progression.15 Therefore, we next set out to elucidate the possible association between monocytes/Mψ and Lenvatinib nmr NK cells in HCC patients, paying particular attention to the tissue microlocalization of those cells (Supporting Fig. 3). Both monocytes/Mψ (CD68+ cells) and NK cells were present throughout the HCC tissues, and
often accumulated in peritumoral stroma (42 ± 7 cells/field and 39 ± 5 cells/field, respectively; n = 10), but not in intratumoral areas (12 ± 3 cells/field and 9 ± 2 cells/field, respectively; n = 10) (Fig. 2A). However, inconsistent with our hypothesis, the level of NK cells, neither in peritumoral stroma nor in the intratumoral region, was associated with the
density of monocytes/Mψ in the same area of HCC tissues (Fig. 2B). Unexpectedly, we observed an inverse correlation between the densities of peritumoral stroma MCE monocytes/Mψ and intratumoral NK cells, but a positive association between the densities of peritumoral stroma NK cells and intratumoral NK cells (Fig. 2B), which suggests that recruiting NK cells are educated by monocytes/Mψ in peritumoral stroma, which in turn lead to NK cell dysfunction in the intratumoral region of HCC tissues. To address that hypothesis, we then analyzed the activation status of NK cells in HCC samples dual-stained for CD57 and CD69 (marker for lymphocyte activation). Most NK cells in peritumoral stroma showed marked expression of CD69 (68.5% ± 6.8%; n = 10), which implies that they acquired an activated phenotype (Fig. 2C). In contrast, the majority NK cells in the intratumoral region were negative for CD69 (6.6% ± 2.1%; n = 10), whereas the NK cells in nontumoral liver exhibited moderate expression of CD69 (23.7% ± 2.6%; n = 10) (Fig. 2C).
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