Tumorigenicity of cells transformed by adenovirus type 12 by evasion of T-cell immunity

Abstract

Evidence is presented that cells transformed by adenovirus type 12 are oncogenic because they escape from T-cell immunity. This effect is brought about by reducing the expression of class I transplantation antigens and is a function of the protein translated from the 13S mRNA, transcribed from early region la. These findings establish a novel mechanism by which transformed cells can acquire an oncogenic phenotype.ADENOvIRUS-transformed rodent cells exhibit variable degrees of oncogenicity, depending on the adenovirus species used for transformation: rat cells transformed by the highly oncogenic adenovirus 12 (Ad12) are highly oncogenic in the syngeneic host', whereas rat cells transformed by the nononcogenic adenoviruses, for example Ad2 and Ad5, are rarely tumorigenic in immunocompetent syngeneic rats2. It has been proposed that cells transformed by the non-oncogenic adenoviruses fail to form tumours because they are more antigenic than are cells transformed by oncogenic adenoviruses and therefore are more readily eliminated by the immune system of the host3. The main evidence supporting this hypothesis is that rat cells transformed by the non-oncogenic Ad2, which are non-oncogenic in immunocompetent rats, do form tumours in immunosuppressed rate and in congenitally athymic nude mice.The adenovirus genes responsible for transformation in vitro are localized in a region near the left end of the viral genome, in a 4-kilobase (kb) DNA segment which comprises the first region of the genome to be expressed in lytic infection, and therefore designated early region I (El). This region consists of two transcriptional units, Ela and Elb (ref. 6). We have recently demonstrated that the difference in oncogenic potential between Ad5-and Ad12-transformed cells in nude mice is determined by the large tumour antigen specified by subregion E1b7'8. We show here that the identity of the Ela subregion determines the susceptibility of transformed cells to the cellular immune system, that is, rat cells expressing Ad5 Ela are highly susceptible to cytotoxic T cells and so are only oncogenic in immunodeficient animals, whereas cells expressing Ad12 Ela have a reduced susceptibility for T-killer cells and hence are oncogenic. By using a set of cell lines transformed by mutant El regions we show that the inactivation of major histocompatibility complex (MHC) class I gene expression is a function of the product of the Ad12 13S Ela mRNA. Oncogenicity of Ad-transformed cellsWe have recently reported the construction of two Ad5Ad12 hybrid early region 1 plasmids: one, pAd512, consisting of the Ela region of non-oncogenic Ad5 and the Elb region of highly oncogenic Ad12; and the other, pAd125, consisting of Ad12 Ela and Ad5 Elb. These plasmids were used to transform primary baby rat kidney (BRK) cells and the oncogenicity of the resulting transformed cell lines was tested in nude mice'. Comparison of the oncogenic potential of the various transformed cell lines in immunocompetent rats and in immunodeficient nude mice (Table 1) revealed a maj...

Construction and characterization of an adenovirus type 5/adenovirus type 12 recombinant virus

“…Virology 127,[45][46][47][48][49][50][51][52][53][54] One possibility is that the identity of the Ela region is important in determining the oncogenic potential of a virus. We have recently found evidence for this hypothesis by showing that adenovirus-transformed rat cells expressing the Ad12 Ela region can escape the thymus-mediated immune surveillance of the syngeneic host, while cells expressing the Ad5 Ela region can not (Bernards et al, 1983b). Another possibility is that early region 3 gene products are involved in the process of tumor induction by the virus.…”

Presentation of CMV immediate-early antigen to cytolytic T lymphocytes is selectively prevented by viral genes expressed in the early phase

“…Because of its selectivity, the inhibition of pp89 presentation is unlike other reported cases of interference with antigen recognition by CTLs, all of which could be explained by a general decrease in the surface levels of ce 1-lular presenting or adhesion moleeules (Gooding, 1982;Bernards et al , 1983;Jennings et al, 1985;Masucci et al , 1987;Gregory et al. 1988) that indiscriminately affects the presentation of any antigen.…”

“…membrane proteins required for the recognition of infected ceUs by cytolytic T Iymphocytes (CTLs). For several viruses (Gooding, 1982;Bernards et al, 1983), including herpesviruses (Jennings et al , 1985;Masucci et al , 1987), defective antigen recognition has been associated with decreased surface levels of MHC class I glycoproteins. For adenoviruses, there is evidence that the underlying mechanism is an active interference with class I mRNA processing (Vaessen et al, 1987) or with glycosylation (Burgert and Kvist.…”

“…1985). A correlation of these tindings with tumorigenicity and evasion of adenoviruses and SV40 from the immune response (Gooding, 1982;Bernards et al, 1983;Tanaka et al, 1985) is a matter of controversy (Haddada et al, 1988).…”

An adenovirus type 5 E1A protein with a single amino acid substitution blocks wild-type E1A transactivation.

“…The ElA proteins also play an essential role in adenovirus transformation (53). Recently, the ElA proteins of a tumorigenic serotype of adenovirus (adenovirus type 12 [Ad12]) were shown to block expression of class 1 major histocompatibility complex (MHC) genes in both rodent and human cells (4,9,54).…”