The differential expression of H‐2K versus H‐2D antigens, distinguishing high‐ metastatic from low‐ metastatic clones, is correlated with the immunogenic properties of the tumor cells

Abstract

Two clones of the 3LL Lewis lung carcinoma, a low-metastatic clone A9 and a high-metastatic clone D122, were studied for MHC expression and immunogenic properties. Using monoclonal antibodies, we demonstrated that the A9 clone expresses both the H-2Kb and the H-2Db, whereas the D122 expresses only the H-2Db, and lacks the expression of the H-2Kb encoded molecules. Cells of the low-metastatic clone A9 grew progressively in syngeneic (C57BL/6J) or in F1 mice, but were rejected in allogeneic recipients. The high-metastatic D122 grew progressively in all mouse strains tested, yet metastases were formed only in syngeneic recipients. When H-2 recombinant mice were used, the A9 again manifested a significantly greater immunogenic potency than the metastatic D122, which grew in all 4 recombinants tested. Metastases, however, were formed in B10HTG and to a lesser extent in B10A(4R), thus indicating that metastasis formation is restricted by both C57BL background and H-2Db sub region. We subsequently tested whether the higher immunogenicity of the H-2Kb-positive A9 cells is expressed also in syngeneic mice, to examine whether this could account for its low metastatic phenotype. We found that immunization by A9 cells significantly inhibited the growth of a subsequent A9 graft and even of D122, yet D122 did not retard the growth of secondary D122 or A9 cells. The increased immunogenic effect was expressed also in the generation of syngeneic cytotoxic lymphocytes by A9 but not by D122 cells. We suggest that expression of H-2K molecules on the 3LL clones, immunogenicity and the metastatic phenotype are causally related in this system.

In vivo H‐2K and H‐2D antigen expression In two allogeneic mouse tumours of low immunogenicity

“…In our own experiments '^^I-3LL cells were lysed in vivo following immunization against D^ but not against K"^, showing that our 3LL line is also K'^-deficient. Eisenbach et al correlated K^-deficiency with poor immunogenicity, since a 3LL clone selected for high K^ expression was more immunogenic in allogeneic mice and showed some indication of immunogenicity in syngeneic mice (7). H-2K expression also appears to be necessary for both induction of CTL and susceptibility to lysis in the response to murine leukaemia virus antigens on syngeneic AKR leukaemias (14).…”

Loss of monomorphic and polymorphic HLA antigens in metastatic breast and colon carcinoma

“…Four (Benacerraf, 1981;Linsk & Goodenow, 1986;Schwartz, 1982). The class I MHC molecule consists of three alpha regimes, covalently linked to beta-2-microglobulin (beta 2m), which are encoded by separate genes, and linked prior to expression at the cell membrane (Ploegh et al, 1981;Arce-Gomez, 1978 (Eisenbach et al, 1983;1985). Studies on the expression of human MHC class I antigens in primary vs metastatic tumour are limited; for example malignant melanoma, digestive tract, and laryngeal tumours (Ruiz-Cabello et al, 1989;Esteban et al, 1989).…”

“…With these immunogenic tumours, those with a high level of MHC antigen expression show low metastatic ability; transfection and subsequent expression of the H2K gene into otherwise highly metastatic H2K-negative tumour cell variants reduces tumour growth, and prevents metastasis (Eisenbach et al, 1983;1985). Studies on the expression of human MHC class I antigens in primary vs metastatic tumour are limited; for example malignant melanoma, digestive tract, and laryngeal tumours (Ruiz-Cabello et al, 1989;Esteban et al, 1989).…”

Modification of PDGFα receptor expression or function alters the metastatic phenotype of 3LL cells

“…Actually, in some experiments the low-metastatic, PDGFa receptor negative A9 clone grew faster than the high-metastatic D122 clone in the footpad. This lack of correlation between metastatic phenotype and growth rates of local tumors was demonstrated before in a large group of 3LL clones (Eisenbach et al, 1984).…”

“…These results suggested there are additional mechanisms contributing to the control of metastatic spread. In our previous studies we have demonstrated that the low metastatic clone A9 expresses much higher levels of MHC class I H-2K b glycoproteins compared to the high metastatic clone D122, resulting in greater immunogenicity of the former (Eisenbach et al, 1984). In fact, immunization of naive C57BL/6 mice with irradiated A9 cells partially retards the development of a subsequent A9 challenge, while immunization with irradiated D122 cells does not a ect the growth of a second D122 tumor (Eisenbach et al, 1984).…”