Nk Cell Trafficking And Cancer Any Relevance

Immunohistologic analysis of leukocytic infiltrates in many human tumors indicates that they are composed mainly of macrophages and CD4+ and CD8+ T-lymphocytes with minor elements of neutrophils, B-lymphocytes, eosinophils, and NK cells (14,35,76,77). This poor representation of NK cells in tumor infiltrates has raised many questions about the importance of their role as antitumor effector cells. However, because NK cells are believed to be a first line of defense against tumors, it may not be unusual for the tumor infiltrates of established tumors to lack these cytolytic cells. A number of reports in experimental rodent models have demonstrated NK cell infiltration only at the early stages of tumor growth and formation, not at the later stages in the tumor lesion (14,76,77). Similarly, during viral infections or allograft rejections, infiltrating NK cells precede T-cell entry into the tissue lesions; however, at later time periods, NK cells were not found in these infiltrates. One possible reason for the absence of NK cells in tumor lesions is the fact that NK cells have shorter life spans than other lymphoid cells and macrophages. Although the half-life of an NK cell has not been clearly defined, it has recently been suggested that NK cells survive only a few days in culture and a few weeks in vivo whereas T-lymphocytes and macrophages may survive much longer (9-12). Perhaps this is one reason that NK cells and the shortlived neutrophils and eosinophils are poorly represented within tumor infiltrates. However, it is also possible that certain tumors are not producing the proper chemoattractants to facilitate leukocyte entry.

Over the past 15 yr, several immunotherapy studies have demonstrated that the systemic infusion of cytokines induced significant changes in the phenotypes of cells within the tumor infiltrate (78). Since IL-2 had been shown to exert profound effects on NK cell activation and proliferation (9-12), it was the hope that systemic IL-2 administration would promote the activation, proliferation, and subsequent trafficking of circulating NK cells into established tumor lesions. Unfortunately, although a substantial increase in the number of circulating CD56+ CD16+ lymphocytes was observed, few

NK cells were observed within the intratumoral infiltrates of treated patients (14,35,79, 80). Similarly, systemic infusion protocols using IL-tp, GM-CSF, IFN-y, and/or TNF-a have also failed to promote increased NK cell trafficking into tumors (35,78).

More recently, cytokine gene transfection into tumors or antigen-presenting cells has led to a more controlled means of introducing specific cytokines into the tumor microenvironment. In these studies, implantation of a cytokine-transfected tumor cell in a host permitted the secretion of high levels of cytokine locally in the tumor area, thus inducing a strong inflammatory response. In contrast to the systemic IL-2 infusion studies, significant lymphocytic infiltrates consisting of both CD4+ and CD8+ T-cells and GM1+ CD56+ NK cells were typically observed in tissue deposits bearing certain IL-2 transfected tumor cells (78,81). In some studies, this tumor cell rejection was highly dependent on the presence of CD8+ T-cells and NK cells (78). However, in other IL-2-transduced tumor models, poor cellular infiltration and poor tumor rejection were observed (14,35,78). In many of these gene-transduced tumor cell studies, the leukocytic infiltrate in the tumor tissue is often quite variable and is highly dependent on a number of factors including the type of tumor utilized, the immunogenicity of the tumor, expression of MHC molecules and T-cell costimulatory molecules on the tumor, the level of tumor vascularization and access, the cytokine being expressed, and the level of cytokine secretion (78). For example, certain IFN-y-transduced tumor cells induce significant T-cell infiltration with few NK cells and neutrophils whereas IL-4-transduced tumors result in a significant eosinophil and macrophage infiltration with few to no lymphocytes and NK cells (14,83).

Since the early 1980s, the adoptive transfer of LAK cells or tumor-infiltrating lymphocytes (TILs) has been performed in a series of cancer patients, resulting in a low but significant proportion of clinical responses, especially in those with renal cell carcinoma and melanoma (35). Critical to the activity of these systemically transferred effector cells is their localization to tumor sites. However, for the most part, the proportion of LAK and TIL cells capable of penetrating tumor tissues is quite small, consistent with several early lymphocyte trafficking studies demonstrating that highly activated T- and mononuclear cells migrate poorly into peripheral tissues and tend to localize in various organs and lymphatic tissues (35).

Overall, the biologic significance of NK cells as antitumor effector cells remains unproven. Their potent tumoricidal activities in vitro suggest that these cells would be capable of fighting established tumors in vivo. Furthermore, the incidence of cancers is higher in animals in which NK cells are depleted or nonfunctional. However, owing to their poor showing in multiple cytokine infusion and adoptive transfer studies in various cancer patients, and until more clearly defined biologic and molecular mechanisms involved in NK cell trafficking are defined, the use of various BRMs and cytokines in cancer patients, with the ultimate goal of specifically targeting NK cells to tumor sites, should be initiated with great caution. Perhaps with a greater definition of chemokine effects on NK cells, we may be able to specifically recruit quiescent and activated NK and LAK cells into tumor lesions and thus facilitate tumor rejection.

Unfortunately, the recent studies of C-C chemokine-transfected tumor cells suggest that this may be "easier said than done" since only modest effects on mouse survival were observed in response to these implanted tumors, despite the fact that significant monocytic and lymphocytic infiltration was observed within the lesions (84,85). Thus, simply getting these various immune cells into the tumors may not be the only problem we are facing in the immune intervention.

By contrast, adoptive transfer of activated NK cells may have a role in certain clinical settings. Abundant preclinical data support a role for these cells in enhancing hematopoietic and immune reconstitution after bone marrow transplantation (82).

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