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In Situ Augmentation of Class I Major Histocompatibility Antigen Expression on Immunogenic Variants of a Spontaneous Murine Mammary Carcinoma¹

Cancer Research Laboratories, Department of Pathology, Queen's University, Kingston, Ontario, Canada K7L 3N6

The relationship between expression of cell surface glycoproteins encoded by the major histocompatibility complex (MHC) and immunogenicity of a recently obtained spontaneous murine mammary adenocarcinoma (designated CBA.SP1) was examined. Immunogenic and nonimmunogenic variant clones were isolated from a subclone of the parent tumor after treatment with the mutagen N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) or the DNA hypomethylating agent and "gene activator," 5-aza-2'-deoxycytidine (5-aza-dCyd). All clones from the untreated tumor population were tumorigenic in normal syngeneic recipients. In contrast, immunogenic variant clones, isolated at high frequencies after drug treatment [ranging from 5% (5-aza-dCyd treated) to greater than 90% (MNNG treated)], were rejected in normal syngeneic mice but grew progressively in T-cell deficient nude mice. Consistent with our previous report (J. Natl. Cancer Inst., 75: 291, 1985), all 5-aza-dCyd induced immunogenic clones expressed elevated levels of class I (particularly D^k) MHC antigens. However some (three out of nine) nonimmunogenic clones also showed enhanced class I MHC expression, implying that not all high MHC expressors were immunogenic. In contrast to 5-aza-dCyd induced variants, only 50% of MNNG induced immunogenic variants showed elevated levels of D^K or D^k and K^k antigens in vitro. Strong augmentation of class I MHC antigens in situ was observed on all immunogenic, but not nonimmunogenic, clones following transplant into syngeneic mice; no increase in MHC expression on variants during progressive growth in athymic nude mice occurred. Although no class II (A^k or E^k) antigens were detected on the parent line or any of the immunogenic variants, a strong infiltration of host I-A bearing cells occurred during immune rejection of SP1 variants. These results are consistent with the hypothesis that induction of class I MHC antigen expression on certain low MHC expressing tumors, although not the sole requirement for immunogenicity, can facilitate immune rejection of the SP1 tumor and, conversely, that the reduced level of MHC observed in certain clinical cancers may significantly affect the immunological aspects of the tumor-host relationship.

¹ This work was supported by grants from the National Cancer Institute of Canada, and the Medical Research Council of Canada.

² Research Associate of the National Cancer Institute of Canada. To whom requests for reprints should be addressed.

³ Present address: Mount Sinai Research Institute, 600 University Avenue, Toronto, Ontario.

Received 7/28/86. Revised 6/ 3/87. Accepted 6/15/87.