Tumour inhibition mediated by BCG in immunosuppressed rats

Abstract

Two rat sarcomas (CC5 and P7) which grow progressively on transplantation into normal syngeneic hosts failed to develop when injected in admixture with the Glaxo strain of Bacillus Calmette-Guérin (BCG). Under comparable conditions, the local development of a third neoplasm (P8) was temporarily inhibited and the number of pulmonary metastases significantly reduced. Experiments were undertaken to determine the extent to which the anti-tumor action of BCG required an immunocompetent host. Rats were immunosuppressed by sub-lethal whole-body irradiation (450 R), with or without prior thymectomy and challenged with inocula of mixed BCG and tumour cells when their capacity to respond to bacterial, tumour and unrelated antigens was maximally depressed. In non-sensitized immunosuppressed rats, the ability of BCG to limit tumour outgrowth was abrogated only in the case of sarcoma CC5. For this neoplasm, immunogenic in syngeneic hosts by conventional criteria, there was a statistically significant difference in the number of tumours in immunosuppressed rats (51%) compared with non-sensitized immunocompetent controls (6%). Presensitization to either bacterial or tumour antigens, prior to thymectomy and/or irradiation, fully restored the tumour-inhibitory capacity of BCG. By contrast, sarcoma P7 was not significantly less susceptible to BCG-induced regression in non-sensitized immunosuppressed rats than in nonsensitized normal rats; and sarcoma P8 similarly failed to reveal any significant differences in susceptibility to BCG affecting primary or secondary tumour development. It is concluded that tumours may vary widely in their sensitivity to host reactions aroused by BCG. Certain neoplasms, exemplified by sarcoma CC5, require participation of an immune reaction of delayed hypersensitivity type for optimal destruction at BCG sites, while for others (e.g. sarcoma P7) an immunoreactive component of this type is not essential. By contrast, a third category of tumour (e.g. sarcoma P8) is relatively resistant to host reactions induced by the mycobacteria. An important component of BCG-mediated tumour inhibition is not dependent on an immunologically intact host.

Influence of whole body irradiation on bcg contact suppression of a rat sarcoma and tumour-specific immunity

“…In the present studies, the level of immunosuppression produced by simple whole body irradiation has not been characterized, but it has been clearly demonstrated that irradiated animals, while rejecting mixed inocula of cells + BCG, fail to develop the systemic tumour immunity normally capable of controlling a simultaneous challenge with tumour cells alone. The present findings and those of Moore et al (1975) demonstrate, therefore, that fundamentally different host responses are involved in these two events and that full host immunocompetence is not necessary for BCG contact therapy. This is further supported by the previous demonstration of BCG contact suppression of rat tumour xenografts in athymic nude mice (Pimm and Baldwin, 1975).…”

“…The present findings and those of Moore et al (1975) demonstrate, therefore, that fundamentally different host responses are involved in these two events and that full host immunocompetence is not necessary for BCG contact therapy. This is further supported by the previous demonstration of BCG contact suppression of rat tumour xenografts in athymic nude mice (Pimm and Baldwin, 1975).…”

“…Tests with transplanted mouse sarcomata (Bartlett, Zbar and Rapp, 1972;Chung, Zbar and Rapp, 1973) demonstrated that immunosuppression by thymectomy and whole body irradiation, or treatment with antithymocyte serum, abrogated the local suppressive activity of BCG. In marked contrast, Moore, Lawrence and Nisbet (1975) have demonstrated that immunosuppression by thymectomy and irradiation does not abrogate the contact suppressive action of BCG( for sarcomata in the rat. In addlition, rat tumour xenografts in congenitallA-athymic (nude) mice are suppressed when cells are transplanted in admixture with BCG organisms (Pimm and Baldwin, 1975) Influence of whole body irradiation on local tumour-suppressive action of BCG.- Table I shows the tumour-suppressive action of BCG where injected s.c. in admixture with cells of sarcoma Mc7 prepared from solid tissue or harvested from in vitro culture into normal rats and animals exposed to 450 rad y-irradiation.…”

“…In marked contrast, Moore, Lawrence and Nisbet (1975) have demonstrated that immunosuppression by thymectomy and irradiation does not abrogate the contact suppressive action of BCG( for sarcomata in the rat. In addlition, rat tumour xenografts in congenitallA-athymic (nude) mice are suppressed when cells are transplanted in admixture with BCG organisms (Pimm and Baldwin, 1975) Influence of whole body irradiation on local tumour-suppressive action of BCG.- Table I shows the tumour-suppressive action of BCG where injected s.c. in admixture with cells of sarcoma Mc7 prepared from solid tissue or harvested from in vitro culture into normal rats and animals exposed to 450 rad y-irradiation. In all tests, with both normal and irradiated animals, admixture with BCG prevented tumour development in almost all rats, tumour cells alone, whether from solid in vivo growths or in vitro culture, growing out in the majority of normal or irradiated animals.…”

“…However, Moore et al (1975), in a series of experiments with transplanted sarcomata in the rat, have shown that immunosuppression by sublethal whole body irradiation, with or without prior thymectomy, did not abrogate the local suppressive action of BCG. In the present studies, the level of immunosuppression produced by simple whole body irradiation has not been characterized, but it has been clearly demonstrated that irradiated animals, while rejecting mixed inocula of cells + BCG, fail to develop the systemic tumour immunity normally capable of controlling a simultaneous challenge with tumour cells alone.…”