Tumors Immune Response To

Karl Erik Hellström and Ingegerd Hellström, Pacific Northwest Research Foundation, Seattle, Washington, USA

Around the turn of this century, Ehrlich postulated that cancer cells can be destroyed by immunological mechanisms, for example, by using antibodies as 'magic bullets'. Cooley then started to treat cancer patients with bacterial toxins and obtained some clinical responses. Today this treatment would be attributed to the effects of 'biological response modifiers'.

It was only when inbred strains of mice became available, however, that workers in this field could critically investigate whether tumors express antigens that serve as therapeutic targets. Using such mice, Gross, Foley, Prehn and others demonstrated in the 1940s and 1950s that tumors induced with chemical carcinogens express antigens that can induce an immune response leading to the rejection of transplanted cells from the immunizing neoplasms. These antigens were referred to as tumor-specific transplantation antigens (TSTAs). Klein et al went one step further by showing that a chemically induced mouse tumor could be rejected also by the very animal in which it had originated, and that the antitumor immune response could be adoptively transferred with lymphocytes. There was little or no cross-reactivity between different neoplasms, even when they had the same morphology and had been induccd with the same chemical agent. It is not surprising, therefore, that attempts to use rumor cells to immunize against chemical carcinogenesis failed.

Another key discovery in tumor immunology was made in 1961 when Sjögren and Habel, working independently, reported that murine neoplasms induced with polyoma virus express TSTAs. Subsequently, TSTAs were detected among murine tumors induced by several other viruses and were found to be shared by tumors induced by the same virus and different among tumors induced by different viruses. Spontaneous tumors, in contrast, did not reveal any TSTA when tested by preimmunization with tumor cells that had been rendered incapable of dividing followed by challenge with live tumor cells. For example, Hewitt investigated 26 different spontaneous mouse tumors and failed to detect any tumor immunity at all; the spontaneous tumors were thus nonimmunogenic (under the conditions tested). Furthermore, the TSTAs in chemically induced rodent tumors were primarily seen in those neoplasms which had been induced by large doses of the carcinogens, while neoplasms induced by small doses either lacked detectable TSTAs or grew even better in immunized hosts than in untreated animals. This was discouraging, since most human tumors are 'spontaneous', and those which are caused by chemical agents probably result from exposure to low doses of such agents. It is also uncertain to what extent there are human neoplasms induced by viruses similar to those causing the expression of strong TSTAs in rodents.

Fortunately, there is now evidence that an immune response can be detected and/or induced against a large variety of tumors, including human tumors, and that the early failures to detect such a response was not due to a lack of tumor antigen, but rather related to the ways tumor immunity was induced. This raises the hope that immunological mechanisms can be utilized towards developing clinically beneficial immunotherapy in humans.

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