Genetic control of in vivo immunity to tumor‐specific transplantation antigens of chemically induced murine fibrosarcomas

Abstract

A possible genetic control of the in vivo immunity to tumor‐specific transplantation antigen (TSTA) of two methylcholanthrene‐induced BALB/c fibro‐sarcomas, C‐1 and ST2, was studied in F1 compatible hosts. Both tumors, which have been previously shown to share their TSTA, lost their immunogenicity in (BALB/c×C3Hf)F1 and C‐1 also in (BALB/c×BALB.K)F1 mice; the immunogenicity of both sarcomas remained unchanged in other hybrid combinations of BALB/c with H‐2b or H‐2a animals. For C‐1 this was true either for a primary immunity to low doses (104 and 5 × 104) of tumor cells or for the secondary immune response measured as a capacity of preimmunized animals to resist a challenge of 105 cells. Since (BALB/c×B10.BR) or (BALB/c×AKR)F1 hybrids (both H‐2d × H‐2k) were able to reject C‐1 cells as strongly as BALB/c mice, the proof of a possible genetic influence involving dominant genes coding for low responsiveness to C‐1 or to ST2 and linked to H‐2k haplotype was sought in a back‐cross experiment. The primary and secondary immune response to C‐1 and the secondary immunity to ST2 were evaluated in BALB/c × (BALB/c × C3Hf) back‐cross mice. Results for both tumors were compatible with the presence of an H‐2 dominant gene (or cluster of genes), whose products suppress immunity to TSTA; the linkage of low anti‐tumor responsiveness with H‐2k was demonstrated for both C‐1 and ST2. Further evidence for this linkage was found in the study of immunity to C‐1 in (BALB/c×C3Hf)×(BALB/c×C3Hf) F2 animals. An attempt to map gene(s) governing the low immune response to C‐1 and ST2 was performed by studying the anti‐tumor immunity of BALB/c, (BALB/c×A), (BALB/c×A.TL), (BALB/c×A.AL), (BALB/c×B10.A), [BALB/c×B10.A(4R) and (BALB/c×C3H.OH]F1 mice. It was found that Kk and Dk regions are not necessary for the low immunity to C‐1 to be expressed, therefore mapping the relevant gene(s) in the Ik region. The low immune response of (BALB/c×C3H.OH)F1 mice to C‐1, however, suggested that Dk genes are also important in this phenomenon. For ST2, only BALB/c×C3H.OH animals showed a low anti‐tumor response thus mapping genes coding for a suppression of anti‐ST2 immunity in the Dk region. Since (BALB/c×B10.A) but not (BALB/c × A)F1 mice (both hybrids having an identical H‐2d × H‐2a genotype but different non‐H‐2 backgrounds) were able to develop an anti‐C‐1 immunity, an effect of non‐H‐2 factors which may counteract the suppressive activity of MHC genes is implied. The possible mechanims of this genetic control are discussed.

Expression of alien minor histocompatibility antigens distinct from tumor‐specific transplantation antigen on a murine fibrosarcoma

“…The loss of TSTA immunogenicity of ST2 in (BALBlc X C3Hf) and (BALB/c X C3H.OH) F1 mice, in fact, was not sufficient to conclude for a sharing of determinants between TSTA and alien non-H-2 antigens since we have recently found that a genetic control of anti-TSTA immunity exists and that (BALBlc X C3Hf) and (BALBlc X C3H.OH) hybrids are among low-responder animals (Parmiani and Ballinari, 1979).…”

“…The F, study showed that (BALBlc X C3Hf) and (BALBlc X C3H.OH) and, to a lesser extent (BALBk X C3H.SW) mice, developed a lower anti-TSTA immune response than did BALB/c mice. This apparent hierarchy of low responsiveness introduced by genes of the C3H background may be due to a regulatory role of H-2 genes on the transplantation immunity to TSTA as suggested by studies on the genetic control of the in vivo immunity to other tumors (Williams et al, 1975;Albright et al, 1977;Parmiani and Ballinari, 1979;Forni et al, 1980). The significant response of (BALBlc X C3H.SW) F, animals to ST2, however, suggested that the minor alien antigens of C3H background do not include a relevant part of TSTA determinants.…”

“…Fibrosarcomas ST2 and C-3 induced by SC application of methylcholanthrene (MCA) (Eastman Organic Chemicals, Chicago, Mich., USA) in our BALBicDp mice were kept in vivo by syngeneic SC passage. Both tumors have individual, distinct TSTA and no alien antigens of H-2 type were detectable on ST2 (Invernizzi et al, 1977b) and C-3 (Parmiani, 1977). ST2 was examined for biochemical markers by Dr. Hans H. Krog (The Fibiger Laboratory, Copenhagen, Denmark) and found to be of BALB/c genotype.…”

“…Both tumors have individual, distinct TSTA and no alien antigens of H-2 type were detectable on ST2 (Invernizzi et al, 1977b) and C-3 (Parmiani, 1977). ST2 was examined for biochemical markers by Dr. Hans H. Krog (The Fibiger Laboratory, Copenhagen, Denmark) and found to be of BALB/c genotype.…”

Tumour antigens and alloantigens. II. Lack of association of rat hepatoma‐D23‐specific antigen with β2 microglobulin

“…The suggestion was made, however, that the tumour-specific antigens of a number of immunogenic murine tumours might be alloantigens foreign to the syngeneic host (Invernizzi and Parmiani, 1975;Parmiani and Invernizzi, 1975;Parmiani, 1977). These studies showed that immunization with some allogeneic tissues could protect against the growth of the syngeneic tumour and that the converse also occurred, i.e.…”