All nascent neoplasms probably elicit at least a weak immune reaction. However, the initial effect of the weak immune reaction on a nascent tumor is always stimulatory rather than inhibitory to tumor growth, assuming only that exposure to the tumor antigens did not antedate the initiation of the neoplasm (as may occur in some virally induced tumors). This conclusion derives from the observation that the relationship between the magnitude of an adaptive immune reaction and tumor growth is not linear but varies such that while large quantities of antitumor immune reactants tend to inhibit tumor growth, smaller quantities of the same reactants are, for unknown reasons, stimulatory. Any immune reaction must presumably be small before it can become large; hence the initial reaction to the first presentation of a tumor antigen must always be small and in the stimulatory portion of this nonlinear relationship. In mouse-skin carcinogenesis experiments it was found that premalignant papillomas were variously immunogenic, but that the carcinomas that arose in them were, presumably because of induced immune tolerance, nonimmunogenic in the animal of origin.

A method of establishing sublines by trocar transplantation in vivo was used to analyze possible cellular heterogeneity with regard to tumor-specific antigens in individual methylcholanthrene-induced sarcomas. Differences in antigenic specificity were found in at least 1 of the 9 pairs of sublines obtained, respectively, from opposite poles of 9 different primary tumors. No evidence suggested such differences among 7 pairs of sublines similarly derived from later transplant generations. The lack of variation in antigenic specificity between members of subline pairs obtained from later transplant generation tumors suggested that antigenic specificity was a stable characteristic. Even when derived from later transplant generations, the sublines of a particular tumor sometimes differed in growth potential, and/or immunizing capacity, and/or responsiveness to immunity. There was little or no correlation between variations in the two parameters: immunizing capacity and responsiveness to immunity. These findings led to the interpretation that immunizing capacity and responsiveness to immunity behaved like partially independent variables, and that variations in these parameters probably depended on factors other than, or in addition to, cellular antigen content per se. The marked, random, spacial heterogeneity revealed within the tumors in cellular growth rate and antigenic properties suggests that changes seen during serial tumor transplantation are probably due to random clonal variation and subsequent selection.

The growths of many and perhaps all tumors may be stimulated rather than inhibited by a quantitatively low level of immunity. The reason tumors have antigens may be that tumors do not develop in vivo in the absence of at least a minimal immune reaction; in this sense, cancer may be considered an autoimmune disease. This review, based largely on the work of our own laboratory, outlines the data showing that the titration of anti-tumor immunity exhibits the phenomenon of hormesis, i.e. the dose-response curve is non-linear such that low levels of immunity are generally stimulatory but larger quantities of the same immune reactants may inhibit tumor growth. Evidence is also reviewed that suggests that the immune response may vary qualitatively and quantitatively during progression, such that there seems to be, during oncogenesis, a very low level of immune reaction that aids initial tumor growth, followed by a larger reaction that may cause remission of early neoplasms, followed, if the neoplasm survives, by a relative immunologic tolerance to the tumor that may be dependent, at least in part, on suppressor cells. This knowledge may help to explain some clinical observations concerning the relationships among tumor types and the organ distribution of metastases.

In this report, we propose a philosophy of treatment that few physicians may be bold enough to actually embrace, but which we believe may eventually find a place in the oncologist's armamentarium. The proposal is based on two assumptions:(1) that many hormones and other biologicals have reverse effects in biologic systems depending on their dosage or concentration, a phenomenon called hormesis; and (2) that most malignant tumors have a large but slow-moving capacity to adapt to adverse conditions, probably by the selection of cellular variants. We suggest that the phenomenon of hormesis might be used to keep a tumor under hormonal and/or immunologic environments that are inimical to its growth and well-being.

INCIDENTAL to investigations of chemical oncogenesis, we have observed that 3-methylcholanthrene (3-MC)-induced subcutaneous sarcogenesis occurred more rapidly in the axillary than in the inguinal region of the mouse. Recently Auerbach et al. have described what may be a similar phenomenon-a marked tendency for tumour transplants to grow better cephalically(1,2).

In this essay I suggest that the major difficulty in producing effective anti-cancer vaccines lies in the fact that most cancers have little immunogenicity because of a basic paucity of tumor-specific antigenicity. The lack of antigenicity, despite extensive genomic instability, could be explained if most tumor mutations occur in silenced genes. A further problem is that an immune reaction against tumor antigens, especially in moderate or low amount, may be stimulatory rather than inhibitory to tumor growth.