A syngeneic model system for the study of tumor metastases and cell-mediated immunity is described. The system consists of two related, chemically induced murine lymphomas, the non-metastasizing parental line Eb and i t s metastasizing variant ESb. A n unrelated, chemically induced tumor (MDAY) i s included for specificity controls. Serological typing revealed that both Eb and ESb were of T lymphoid origin and expressed the H-2K and H-2D molecules of the host strain DBA/2. By various electron microscope techniques, morphological differences were observed between the t w o cell lines. I n comparison t o Eb cells, ESb tumor cells had a more polymorphic nucleus with many invaginations of the nuclear envelope and a more prominent expression of microvilli on the cell surface. A n in vitro organ culture test for tumor invasiveness, presented here for the f i r s t t i m e In a syngeneic murine system, revealed that ESb but not Eb tumor cells had the ability t o attach t o and invade normal tissue. Accordingly, ESb tumor cells showed higher malignancy in vivo. This was apparent from their higher tumorigenicity and their ability t o disseminate and metastasize and t o kill recipient mice more quickly. Upon histological examination of the local primary tumors a striking difference was noticed with regard t o the degree of infiltration by host-derived mononuclear cells, mostly histiocytes. The non-metastasizing tumor Eb was heavily infiltrated while tumor ESb contained only a few of these cells. The differences between the tumor lines ESb and Eb are considered i n the light of their possible relevance for metastases in general. The etiology of the t w o tumors i s discussed in particular with respect t o their relatedness.Metastasis, the spread of malignant cells from a primary site to distant organs, represents one of the most intriguing problems in the pathogenesis and treatment of cancer (see Willis, 1973;Fidler and Kripkie, 1977; Carter, 1978). While primary tumors in many instances can be removed surgically it is the subsequent development of metastases which often cannot be prevented and is responsible for most therapeutic failures (Krokowski, 1978). In spite of its importance, relatively little is known about the processes which either lead to or prevent formation of tumor metastases. One reason for this is that experimental tumors in animals are often not suitable for the study of metastasis: they either do not metastasize or they grow so fast that they kill the host before metastases can develop (Kim, 1970;Mellgren, 1976 The majority of experimental tumors induced by either tumor viruses or chemical carcinogens and maintained by long-term transplantations usually express immunogenic tumor-associated transplantation antigens (TATA) against which syngeneic animals can be successfully immunized. When similar immunization procedures were applied to humans, a significant protective effect was observed only occasionally (see Terry and Windhorst, 1978). The meager success in cancer patients of specific immunotherapy prot...
The syngeneic cytotoxic T-cell response against a metastasizing murine lymphoma variant was investigated and compared with the response against the non-metastasizing parental tumor line Eb. Anti-tumor cytotoxicity was not detectable in a 4-h 51Cr release assay in spleens taken directly from tumor-bearing animals (primary CMC). After restimulation in vitro (secondary CMC) however, high anti-tumor cytotoxic activity was detected. This activity was mediated by immune T lymphocytes as shown by its sensitivity to treatment with anti-Thy 1.2 serum and complement. Ten cells of the metastasizing tumor ESb, inoculated subcutaneously, were sufficient to raise a local tumor and metastases and to induce cytotoxic T memory cells in the spleens. In contrast, about 104 cells were required to raise a local tumor and to induce splenic cytotoxic T memory cells, when the parental tumor Eb was tested. The specificity studies of the anti-tumor cytotoxic activity demonstrated that cytotoxic T cells could distinguish unrelated, chemically induced syngeneic tumors and also recognize antigenic differences between the parental tumor Eb and its variant ESb. Eb and ESb tumor cells were recognized as carrying distinct antigens at the responder cell level, the stimulator cell level and the target cell level. The in vivo significance of these findings is discussed.
In an attempt to analyze mechanisms of immunity against tumor metastases, protective anti‐tumor immunity in vivo was compared with cytotoxic T‐cell activity in vitro in a well‐defined syngeneic tumor model system. The system consists of a chemically induced parental tumor cell line (Eb) with little or no metastatic potential and a spontaneous variant thereof (ESb) with pronounced metastatic properties. Tumor protection experiments revealed the presence of tumor‐associated transplantation antigens (TATAs) on both Eb and ESb tumor cells. TATAs of Eb and ESb were found to be distinct and non‐cross‐reactive. One of several unrelated tumors, however, RL♂1, expressed TATAs which cross‐reacted with those of Eb. Protective immunity against the non‐metastasizing tumor was much stronger than that against the metastasizing variant. Furthermore, the optimal procedures for induction of immunity in vivo were strikingly different for each tumor. Tumor‐specific cytotoxic T lymphocytes (CTLs) were obtained after sensitization in vivo with viable tumor cells and restimulation in vitro for 4–5 days with mitomycin‐C‐treated autologous tumor cells. Both anti‐Eb and anti‐ESb CTLs showed high cytolytic activity in a 4‐h 51Cr release assay against the autologous tumor lines. The target antigens recognized by these cells were similar to the TATAs as defined in the protection experiments. (1) The target antigens of Eb and ESb were distinct and non‐cross‐reactive. (2) Only one of 14 unrelated syngeneic and allogeneic tumors expressed a target antigen which cross‐reacted with that of Eb. (3) This tumor was the radiation‐induced BALB/c lymphoma RL♂1 which also cross‐reacted at the level of the TATAs. The correlations between protective immunity obtained in vivo and cytolytic T cells induced in vitro suggest that cytolytic T cells can recognize TATAs and may thus play an important role in the establishment of protective immunity.
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