Oncogenicity of human papillomavirus- or adenovirus-transformed cells correlates with resistance to lysis by natural killer cells

Abstract

The reasons for the dissimilar oncogenicities of human adenoviruses and human papillomaviruses (HPV) in humans are unknown but may relate to differences in the capacities of the E1A and E7 proteins to target cells for rejection by the host natural killer (NK) cell response. As one test of this hypothesis, we compared the abilities of E1A-and E7-expressing human fibroblastic or keratinocyte-derived human cells to be selectively killed by either unstimulated or interferon (IFN)-activated NK cells. Cells expressing the E1A oncoprotein were selectively killed by unstimulated NK cells, while the same parental cells but expressing the HPV type 16 (HPV-16) or HPV-18 E7 oncoprotein were resistant to NK cell lysis. The ability of IFN-activated NK cells to selectively kill virally transformed cells depends on IFN's ability to induce resistance to NK cell lysis in normal (i.e., non-viral oncogene-expressing) but not virally transformed cells. E1A blocked IFN's induction of cytolytic resistance, resulting in the selective lysis of adenovirus-transformed cells by IFN-activated NK cells. The extent of IFN-induced NK cell killing of E1A-expressing cells was proportional to the level of E1A expression and correlated with the ability of E1A to block IFN-stimulated gene expression in target cells. In contrast, E7 blocked neither IFN-stimulated gene expression nor IFN's induction of cytolytic resistance, thereby precluding the selective lysis of HPV-transformed cells by IFN-activated NK cells. In conclusion, E1A expression marks cells for destruction by the host NK cell response, whereas the E7 oncoprotein lacks this activity.

Dissimilar Immunogenicities of Human Papillomavirus E7 and Adenovirus E1A Proteins Influence Primary Tumor Development

“…Levels of E7 oncoprotein expression in MCA-102-E7-CL1 and MCA-102-E7-CL2 were compared to those in SiHa and H4-E7. SiHa is an HPV16-transformed human cervical cancer line that expresses low levels of HPV16-E7, whereas H4-E7 is an HPV16-E7transfected human fibrosarcoma cell line that expresses high levels of E7 (Routes and Ryan, 1995). As shown in Fig.…”

“…There are several examples of this correlation between the ability of a DNA viral oncogene to induce cellular sensitization to NK killing and the tumor-inducing capacity of the oncogene-ex-pressing cell in the immunocompetent animal. This correlation has been reported for hamster and mouse cells expressing Ad2/5-E1A (NK susceptible and nontumorigenic), hamster and mouse cells expressing Ad12-E1A (NK resistant and tumorigenic), SV40 T antigen-expressing hamster cells (NK resistant and tumorigenic), SV40 T antigen-expressing mouse and rat cells (NK sensitive and nontumorigenic), polyoma T antigen-expressing hamster cells (NK resistant and tumorigenic), and human cells expressing HPV16-or HPV18-E7 and -E6 (NK resistant and tumorigenic) (Cook et al, 1980(Cook et al, , 1982Cook and Lewis, 1984;Fresa et al, 1987;Raska and Gallimore, 1982;Routes and Ryan, 1995;Sawada et al, 1985). The data reported here extend this correlation to E7-expressing MCA-102 cells (NK resistant and tumorigenic) and suggest that this same pattern of resistance for HPV16or HPV-E7-expressing human tumor cells may be relevant in vivo.…”

“…In previous studies we showed that the oncogenicities of HPV-or Ad-transformed human cells correlated with their resistance to lysis by human NK cells (Routes and Ryan, 1995). Oncogenic, HPV transformed human cells were resistant to NK lysis, whereas Ad-transformed human cells were NK sensitive.…”

“…The methylcholanthrene-induced sarcoma cell line MCA-102 was provided by Dr. Nicholas Restifo (National Institutes of Health, Bethesda, MD) (Mule et al, 1987). H4-E7 cells are HT1080-derived, human fibrosarcoma cells expressing high levels of the HPV16-E7 oncoprotein (Routes and Ryan, 1995). MCA-102 cells expressing Ad5-E1A or HPV16-E7 were derived from clones selected in G418 following transfection with pLSXN16E7 or pE1Aneo, which code for G418 resistance and HPV16-E7 or Ad5-E1A, respectively.…”

HPV innate immunity

“…Abrogation is associated with a restricted ability of the NK cells to recognize specific target cells (120). Interestingly, cells transformed by the adenovirus 5 E1A gene are sensitive to NK lysis, whereas the same cells transformed by HPV-16 E7 are resistant (121), and this difference has been shown to correlate with malignant potential in mice (122). In this regard, soluble E6 and E7 oncoproteins of HPV-16 inhibit the ability of NK cells to produce IFN in an in vitro assay (64).…”