#149 New Strategy for Tumor Immunotherapy: Correlation of Natural Killer Cell (NK)-Sensitivity with Lymphotropic Metastatic Potential in Human Carcinoma Cells, Rendering their Suppression and Eradication by the Activation of T-cell Independent, NK-mediated Innate Immunity.
Untae Kim , Anti-Metastasis Systems, Snyder, NY 14226 (untaekim@cs.com)
For many years, cancer researchers have xenografted human tumor cells in athymic nude mice as surrogate hosts to isolate them, but we have also learned that some of them, especially, carcinoma cells are difficult to grow or non-tumorigenic in nude mice, with the acceptance rate ranging from 8.6% for breast, and up to 30% for colon cancer (Fogh, 1980). However, such xenograft-resistance can be overcome by injections of anti-mouse NK antibodies, suggesting that it may be characterized as "NK-sensitive," and the ready acceptance as "NK-resistant". The anti-NK treatment may revive and keep the sensitive cells grow as long as the treatment is continued. When it is stopped, the tumor would regress, but some seem to remain viable but dormant in the nude host for as long as 3 months. Beyond 3-months, however, the tumor cells are no longer revivable.
By applying these procedures, several sets of NK-sensitive and resistant clones of human carcinoma cells have been isolated from the ATCC cell lines, e.g., SW-480 (colon), MDA-MB-231 (breast), PC-3 (prostate), and others, designating each with a suffix -NKS or -NKR, respectively. They are maintained in vitro and in vivo cell lines. Immunochemical analyses of NKS human tumor cells showed markedly elevated EGFR, ZAP-70, CD-54, CD-40, CD-4, and other activated T-cell associated molecules on their surface, while on NKR cells these markers are either absent or very low, implicating their role in the lymphotropic migration of tumor cells, as well as, some may be serving as the target for T-independent, innate anti-tumor immunity.
A similar observation was made with the highly realistic, spontaneously metastasizing rat mammary tumor SMT-2A & TMT-081, vis-à-vis human breast cancer, developed in W/Fu rats, when xenografted in nude mice, along with the non-metastasizing control tumor MT-W9B & MT-100 (Kim, 1970, 1977, 1982, 1986). The NK sensitivity was found only in the lymphotropic tumors, and the non-metastasizing and even hematogenously metastasizing ones were NK resistant. In addition, the tumor angiogenesis seemed to be inversely correlated with lymphotropic metastatic potential (Jirtle, 1981; Yatvin, et al., 1987; Kim, et al., 1988). When the regressed, NK-sensitive, lymph node metastasizing rat mammary tumor SMT-2A cells in nude mice were revived by the anti-NK antibody, and reimplanted back into normal W/Fu rats, they promptly grew and metastasized to regional lymph nodes, as its parent tumor cells did, indicating that the process of xenograft, regression and resuscitation did not alter their original biological, biochemical or immunological properties. Thus, it is further concluded that NK-sensitivity is directly correlated with inherent lymphotropic metastatic potential and NK-resistance with the lack of such property.
When the lymphotropic/NK-sensitive rat mammary tumors grown in W/Fu rats were treated with thymectomy and Cyclosporine-A, the growth of tumor and the development of regional lymph node metastasis was markedly delayed (Kim, et al., 1984). Perhaps, bone marrow-derived NK cells and human D56brightCD16neg together with nitric oxide may be tested in the rat tumor models. We hope these studies would lead to the discovery of new T-cell suppressors and NK-stimulants for generating potent T-independent, NK-mediated innate immunity in human patients, resulting in the eradication of metastatic carcinoma cells.
