Studies of Thymic Function with Emphasis on the Role of the Thymus in Oncogenesis¹

The genetically controlled variation in mice to polyoma virus tumor induction which appears to be determined by 1 or a few genes is not a property of individual target cells or of individual cells which influence viral growth patterns. It thus differs from the susceptibility and resistance to virus infection studied by Bang and Warwick (4), Goodman and Koprowski (27), and Rubin (91). As mentioned previously, isolated organ cultures of C57BL mice transform readily to neoplasia in the presence of polyoma virus; resistance is therefore a characteristic of the intact animal.

It is clear from the facts presented in this study that the most plausible explanation for resistance to polyoma virus oncogenesis is related directly to the immunologic capacity of the host animal; cellular immunity of the homograft type invoked against virus-specific “tumor” antigen contained in neoplastic cells is involved. In the immunologically disturbed animal (following neonatal thymectomy) these “tumor” antigens are not capable of invoking an effective immunologic attack on clones of cells transformed to neoplasia by polyoma virus. Neoplastic clones therefore grow progressively into frank neoplasms. In the immunologically competent animal, either intact or restored neoplastic conversion occurs, but such cells are aborted by a successful homograft-type reaction. Immunologic restoration was accomplished in the thymectomized C57BL mouse by all 3 of the methods attempted to the extent of permitting adequate homograft rejection and thus repressing the origin of neoplastic cells. C57BL mice are known to become immunologically competent soon after birth (76).

The immunologic deficit resulting from thymectomy at 3 days of age which allows tumor induction by polyoma virus is indeed quite subtle and not easily recognized grossly. Little or no lymphoid cell depletion was noted and these mice (C3H and C57BL) were quite capable of rejecting allogeneic skin grafts and of forming in normal fashion hemolysins and agglutinins to sheep erythrocytes and HI antibodies to polyoma virus. C57BL female mice thymectomized at 3 days, however, were less capable of rejecting male skin than their intact littermates. Twelve thymectomized females rejected male skin at an average time of 68 days, whereas all 15 intact control littermates had rejected skin grafts by 30 days.

These results suggest that the polyoma virus-specific “tumor” antigen is functionally similar to a minor histocompatibility antigen.

It should be reemphasized that resistance and susceptibility to tumor induction by polyoma virus are unrelated to viral growth patterns and to humoral antibody production to virus. The patterns were nearly identical in intact and thymectomized C57BL mice. These findings also suggest that a difference in interferon production is not a major factor in increased susceptibility to polyoma virus.

Thymic tissue per se is a necessary antecedent of resistance to polyoma virus tumor induction to the extent that it provides maturation of immunologic faculties and consequently prevents the progression of neoplastic clones of cells induced by virus. If many tumors contain “tumor” antigens foreign to the host, it is likely that the host can respond immunologically against these antigens and destroy or inhibit emerging clones of neoplastic cells. Neonatal thymectomy should therefore induce an increased susceptibility to the development of such tumors. The generality of the influence of thymectomy remains to be determined. Early thymectomy in the rat and hamster is associated with an increased sensitivity to polyoma virus (16, 102). Neonatal thymectomy in the Syrian hamster did not influence induction by RSV of gliomas or of fibrosarcomas (G. Rabotti and L. W. Law, unpublished observation), nor was there observed an increased yield or lowered latent period in mammary carcinoma induced by the Bittner virus or in MCA-induced fibrosarcomas as revealed in this study.

Early in the discussions of polyoma virus tumor induction it was pointed out that the striking sensitivity of newborn animals may be related to the fact that the most responsive tissues were still in an embryonal and undifferentiated state (14, 34); neoplastic transformation did not usually occur in mice and hamsters older than 20 days since differentiation of the susceptible tissues had already occurred at this time. The results discussed here showing that C3H mice infected “spontaneously” as adults can readily become tumorous provided an immunologic deficit is created through neonatal thymectomy appear to rule out such a concept.