Role of NK Cell Subsets in Organ-Specific Murine Melanoma Metastasis

Abstract

Tumor metastasis plays a major role in the morbidity and mortality of cancer patients. Among solid tumors that undergo metastasis, there is often a predilection to metastasize to a particular organ with, for example, prostate cancer preferentially metastasizing to bones and colon cancer preferentially metastasizing to the liver. Although many factors are thought to be important in establishing permissiveness for metastasis, the reasons for organ-specific predilection of each tumor are not understood. Using a B16 murine melanoma model, we tested the hypothesis that organ-specific NK cell subsets play a critical role in organ-specific metastasis of this tumor. Melanoma cells, given intravenously, readily colonized the lungs but not the liver. NK cell depletion (either iatrogenically or by using genetically targeted mice) resulted in substantial hepatic metastasis. Analysis of NK cell subsets, defined by the differential expression of a combination of CD27 and CD11b, indicated a significant difference in the distribution of NK cell subsets in the lung and liver with the mature subset being dominant in the lung and the immature subset being dominant in the liver. Several experimental approaches, including adoptive transfer, clearly indicated that the immature hepatic NK cell subset, CD27+ CD11b–, was protective against liver metastasis; this subset mediated its protection by a perforin-dependent cytotoxic mechanism. In contrast, the more mature NK cell subsets were more efficient at reducing pulmonary tumor load. These data indicate that organ-specific immune responses may play a pivotal role in determining the permissiveness of a given organ for the establishment of a metastatic niche.

Intratumoral natural killer cells show reduced effector and cytolytic properties and control the differentiation of effector Th1 cells

“…6 Our data have shown for the first time that a significantly high number of CD27 NK cells are preferentially recruited into the B16F10-induced melanoma tumor microenvironment at an early stage. Our data are in contrast with previous report by Lakshmikanth et al which observed very few NK cells among leukocytes in mouse primary melanomas.…”

“…4 Infiltration of NK cells has been observed in several types of tumors such as fibrosarcoma, renal cell carcinoma, gastrointestinal sarcoma, and breast tumors. 5,6 The CD27…”

NK Cells Are Required for Dendritic Cell–Based Immunotherapy at the Time of Tumor Challenge

“…In addition, NK cells at distinct anatomic locations inhibit B16 using different mechanisms. For example, liver NK cells, but not lung NK cells, rely on perforin-dependent pathways for destruction of B16 (46).…”

“…These features may protect B16 from direct NK cell cytolysis. It is also noteworthy that NK cells isolated directly ex vivo are only poorly cytotoxic against B16, unless isolated from hosts systemically activated with polyinosinic-polycytidylic acid or CpG (46,49).…”

Monomethyl fumarate augments NK cell lysis of tumor cells through degranulation and the upregulation of NKp46 and CD107a

“…2 NK cells also have immunoregulatory features, including the secretion of cytokines and chemokines and cell-to-cell cross-talk, 3,4 and are important in defending against viral infections and controlling tumor growth. 5,6 The activities of NK cells are regulated through activating and inhibiting receptors, which determine the course of action of these cells. 7 NK cells are activated through distress via the detection of stress-induced ligands on target cells by NK cytotoxicity receptors, which include NKp30, NKp44, NKp46 and C-type lectin receptors, such as NKG2D.…”