Immunostimulation of cancer versus immunosurveillance.

A moderate antitumor immune reaction is optimal for tumor growth and most (perhaps all) untransplanted tumors, rather than being inhibited, are probably dependent, at least early in their progression, upon the immune reaction. Some tumors, as for example most human skin tumors, have a higher incidence in immunodepressed patients than they do in the general population. This could mean that the normal immune reaction usually inhibits the growth of these tumors. More probably, the increased incidence in immuno-depressed heart and kidney transplant patients is caused by a lowering of a tumor-stimulatory immune reaction to a level that is even more stimulatory. Other tumors, such as human mammary tumors, have, in contrast to the skin tumors, a lower than expected incidence in immunodepressed patients. Mammary tumors are postulated to possess, on average, a low immunogenicity that arouses an immune reaction that is usually equal to or less than that required for optimal tumor growth; a further lowering of the reaction, as occurs in heart or kidney transplant patients, thus results in a lowered tumor incidence. In such patients, an immunostimulating adjuvant or vaccine might, we predict, sometimes accelerate rather than inhibit tumor growth.

The flip side of tumor immunity.

A large amount of data suggest that tumors are, to some degree, dependent for their growth on a positive level of immune reaction, a level that is unique for each tumor. Each tumor gradually adjusts its immunogenicity to the level that will, in the immunologic context of its own particular host, maximize its growth. Thus, it follows that immunosuppression may be as likely as immunoaugmentation to have a therapeutic effect.

The autoimmune nature of cancer.

Four different kinds of data from the 3-methylcholanthrene-induced sarcoma system of the mouse show that the immune system stimulates oncogenesis; i.e., the presence of a tumor-specific immune reaction is a positive aid to tumor development. It seems proper, therefore, to consider cancer, at least in part, an autoimmune disease.

The immune basis of dosage-induced reversal of the rank-order of strain susceptibility to MCA.

Even AHH-inducible mouse strains vary in their susceptibilities to MCA sarcomagenesis. Previous work showed that the rank-order of strain susceptibility depended upon the dosage of MCA; the strain most susceptible to a high dose became the least susceptible to a low one and vice versa. We now confirm our previous findings and test the hypothesis that the reversal, with dosage, of the rank-order of relative strain-susceptibility has an immunological basis. This was tested in two ways: by examining the effect of immunosuppression on strain-susceptibility to sarcomagenesis and by transplanting parental bone marrow into irradiated F1 hybrid to see if the relative MCA-susceptibility characteristics of the parental donors could be transferred. The results of both studies suggest that the rank-order-reversal phenomenon is caused, at least in part, by differences in the immunological reactivities of the strains. Inasmuch as immunosuppression inhibited the response of the C3 mice to a high dose of carcinogen, but facilitated carcinogenesis among the B6, the level of innate immune capacity most conducive to high-dose carcinogenesis is apparently intermediate between the levels of these two strains.

Paradoxical effect of three-day thymectomy on sarcogenesis in the mouse with different dosages of methylcholanthrene.

Past studies have shown that thymectomy in the mouse at 3 days of age but not at birth or after 7 days produces, in later life, a variety of localized autoimmune lesions. In the present work, 3-day thymectomy facilitated subsequent sarcogenesis by low dosages of 3-methylcholanthrene but inhibited oncogenesis by a high dosage. If the presence of autoimmunity implies an increased antitumor immunity, it then follows that increased immunity facilitated low-dose sarcogenesis but inhibited sarcogenesis with a high dose.

Production of autoimmune gastric hyperplasia in mice by the transfer of spleen cells from thymectomized donors.

Previous work showed that mice that had been thymectomized at 3 days of age tended, in later life, to develop a hyperplastic autoimmune gastritis and were also hypersusceptible to sarcogenesis by low dosages of 3-methylcholanthrene. In the present work, it was found that the hyperplastic autoimmune gastritis could be transferred with great efficiency with spleen cells obtained from 3-mo-old donors that had been thymectomized at 3 days of age, but which had not, at the time of transfer, themselves developed overt disease. The recipients were 1-mo-old syngeneic mice that had been made receptive by thymectomy during the first day of life, a procedure that does not, of itself, cause autoimmune disease. The high efficiency of the transfer suggests that, during the transfer process, effector cells may have been differentially favored as compared with the suppressor cells that, in normal animals, supposedly prevent autoimmunity. The practicality of the transfer technique should permit an investigation of the cellular basis of the autoimmunity and the associated increased susceptibility to low-dose hydrocarbon sarcogenesis.

Rank order of sarcoma susceptibility among mouse strains reverses with low concentrations of carcinogen.

Ten mouse strains in which aryl hydrocarbon hydroxylase can be induced, or F1 hybrids of these strains, were ranked according to their sarcoma susceptibility when exposed to a high concentration (5 percent) of the chemical carcinogen 3-methylcholanthrene. This rank order was reversed when the concentration of 3-methylcholanthrene was reduced to 0.05 percent.

Primary tumor immunity in nude mice.

Tumor implants grew better in radiated or in newborn nu/nu mice than in adult nu/nu controls when, and only when, the tumors were demonstrably immunogenic in normal mice. This result suggests primary immunity. No evidence of immunological memory was found by immunization-challenge type experiments in the nude mice.

Immunostimulation of highly immunogenic target tumor cells by lymphoid cells in vitro.

A highly immunogenic mouse tumor was studied with the use of microcytotoxicity test, performed at lymphoid cell:target tumor cell ratios ranging from 1:1 to 1,000:1 at various times during tumour growth and after tumor excision. Although the tumor was highly immunogenic, in vitro lymphoid cell-mediated cytotoxicity was shown only with lymphoid cells from hyperimmunized mice, i.e., mice that had "seen" the tumor more than once. Instead, the lymphoid cells harvested 2 and 3 weeks after tumor inoculation, as well as after excision of the tumor, stimulated the target cells. At 4 weeks after inoculation of the tumor, there appeared to be neither stimulation nor inhibition of the target tumor cells, though at this point the growth of this highly immunogenic tumor had been arrested in vivo.

Intralesional BCG in the treatment of metastatic malignant melanoma.

The therapeutic efficacy of intralesional BCG (Bacillus Calmette-Guerin; one immunizing dose every 2 weeks for a minimum of five treatments) was studied in 19 melanoma patients. Of 15 patients evaluable for response, five experienced significant objective improvement (two complete and three partial remissions). Objective improvement was limited to those patients with dermal metastatic disease. In vitro cytotoxicity in the presence of patient's serum bore, on average, a relationship to the clinical disease. In certain individual cases, serum blocking and/or lymphocyte stimulation may have had prognostic significance.