Immunologic factors involved in the growth of primary tumors in human or animal hosts

An international conference on this topic, sponsored by the American Cancer Society and arranged by Herbert F. Oettgen and George Klein, was held at the Westchester Country Club in Rye, New York, on February 2-4 , 1969. When this conference was planned by the Council of Analysis and Projection of the American Cancer Society, it was emphasized that the primary tumor should be the central theme and that studies using transplanted tumor should be discussed only if they contributed information or methods of immediate relevance to the relation of the primary tumor to its host. Much has been learned in the last 10 years about the capability of grafted experimental tumors to evoke rejection responses in genetically compatible (syngeneic) recipients. In spite of these advances it is not known whether the rejection mechanism actuated by surface antigens of the grafted tumor cells in the syngeneic host is also operative in the animal that bears the primary tumor. Obviously, the latter is confronted with its own antigenic tumor cells in a way quite different from the situation in experiments using isografts with regard to factors such as time, site, antigen release, and general immunologic reactivity. New terms are needed to describe this relation. In syngeneic systems tumor-specific transplantation antigen is the term most commonly used with respect to the new surface antigens of tumors. The word transplantation, however, denotes a definition based on a grafting experiment, which, even if performed in the primary host, does not, in the strict sense, answer the question of whether and to what extent the primary host can mobilize a rejection response against its own tumor cells as they increase in number at their natural pace and at their site of origin. No short name has yet been suggested for this type of "tumor-specific antigen with a rejection-inducing potential in the autochthonous host. " The conference was arranged in four sessions, each concerned with a separate aspect of the main theme. The skeleton of these sessions was provided by brief formal presentations, but more time was spent with extended discussions. As the number of participants was limited to 49, a lively exchange of views was possible. The first session (Chairman, L. J. Old) was devoted to the question of whether serologic studies provide evidence for immune reactions to primary tumors. Research in this area has been greatly stimulated by demonstrations of tumor-specific antibodies in the serum of apparently normal experimental animals or of animals with tumors, i.e., in circumstances that have not involved the use of transplantation or of deliberate immunization. These findings in experimental systems-all concerning tumors and leukemias induced by viruses-have provided an encouraging background to the search for tumorspecific antibodies in man. Burkitt's lymphoma has been a favorite subject of investigation because (a) a herpes virus seems to be associated with the disease and (b) instances of spontaneous tumor regression as well as an unusually good response to chemotherapy have been reported, suggesting the possibility that the tumor is subject to control by an immunologic mechanism. In at least two instances tetraploid ceUs were found in tumors that recurred after a long-term remission. This is most unusual for this type of tumor and, again, indicates the possibility of immunoselection of resistant variants with an increased number of chromosomes, an event known to occur in certain experimental systems. The present status of the serologic studies concerned with Burkitt's tumor was discussed by W. Henle, G. Klein, and L. Old, who have investigated what may be three different antigenic systems associated with Burkitt's lymphoma cells. These are the main facts: (a) Burkitt lymt~homa cells maintained in tissue culture carry the herpes-type Epstein-Barr virus (EBV), and the sera of all patients with this tumor contain antibodies to the virus in high titers; this has been demonstrated by means of indirect immunofluorescence on fixed tissue culture cells (W. and G. Henle). (b) Antibodies to surface antigens of autochthonous and allogeneic Burkitt lymphoma cells have been demonstrated in the sera of patients with Burkitt's lymphoma by means of the membrane fluoresence technic (G. Klein). The titers of these antibodies fluctuate in the course of the disease in a way that appears to be related to the regression or progression of the tumor. In addition, a gradual accumulation of immunoglobulin coating the surface of the tumor cells in vivo has been observed as the disease progressed, and the C'I binding capacity of the tumor cells has frequently paralleled the degree of immunoglobulin coating (Tachibana). About 80% of the sera that contain high titered EBV antibody also react with antigens on the surface of cells carrying EBV. (c) Precipitating antibodies to antigen prepared from an established culture line (P3J) of Burkitt's lymphoma cells have been demonstrated in Ouchterlony tests with sera of many patients with Burkitt's lymphoma (L. Old). Surprisingly, a high incidence of positive reactions was also found in a survey of sera from patients with nasopharyngeal cancer in Africa, Asia, and America. This has provided an unexpected link between two neoplastic diseases which appeared to have nothing in common. More recently, the sera of patients with nasopharyngeal carcinoma have also been shown to contain EBV antibodies in high titers. A comparison of the results of the membrane fluorescence and immunodiffusion tests with those of the test for EBV antibody has shown agreement in many, but not all instances, and the relation of the former two methods to the EBV (and to one another) needs to be further clarified. With regard to the role of the EBV virus in the pathogenesis of Burkitt's lymphoma, it is still uncertain whether the virus is merely a passenger or whether it is a contributing factor in the etiology of this disease. The role of the EBV in the pathogenesis of infectious mononucleosis has been well documented by